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Cancer poses a significant global public health challenge, with commonly used adjuvant or neoadjuvant chemotherapy often leading to adverse side effects and drug resistance. Therefore, advancing cancer treatment necessitates the ongoing development of novel anticancer agents with diverse structures and mechanisms of action. Natural products remain crucial in the process of drug discovery, serving as a primary source for pharmaceutical leads and therapeutic advancements. Triterpenoids are particularly compelling due to their complex structures and wide array of biological activities. Recent research has demonstrated that naturally occurring triterpenes and their derivatives have the potential to serve as promising candidates for new drug development. This review aims to comprehensively explore the anticancer properties of triterpenoids and their synthetic analogs, with a focus on recent advancements. Various aspects, such as synthesis, phytochemistry, and molecular simulation for structure-activity relationship analyses, are summarized. It is anticipated that triterpenoid derivatives will emerge as notable anticancer agents following further investigation into their mechanisms of action and in vivo studies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Six new Pd(II), Pt(II) and Ag(I) complexes, (1);{Pd (L 1 )]2C 6 H 4 } 2 Cl 4 } (2); Pt(L 2 )(DMSO)Cl; 3; {PtL 5 ] 2 C 6 H 4 } 2 ·PhCOO - ⋅11NO 3 - ; 4; {[Pt(L 4 )] 2 C 6 H 4 }; the binuclear cyclometalated complex the polymer chain (5); {[PtL 5 ]C 6 H 4 }·NO 3 - }; and the polymeric silver species (6); Zn(L 6 ) 2 ·AgNO 3 ·CHCl 3 were synthesized and thoroughly characterized using X-ray diffraction and spectroscopic techniques (L 1 =(S,S)-1,4-i-PrOx] 2 C 6 H 4 } 2 Cl 4 , L 2 =Di(2,2-bis(4R-isopropyl-4,5-dihydro-oxazol-2-yl)acetonitrile) zinc (II) (B R1 );L 3 = 1,4-bis(4R-benzyl-4,5-dihydro-oxazol-2-yl)benzene (A R2 ); L 4 = 1,4-bis(4R-benzyl-4,5-dihydro-oxazol-2-yl)benzene，L 5 =1,4-bis(4R-benzyl-4,5-dihydro-oxazol-2-yl)-benzene，L 6 =Di(2,2-bis(4S-isopropyl-4,5-dihydrooxazol-2-yl)acetonitrile) zinc (II). Complexes 1-6 showed cytotoxic effects against human tumour cell lines, including a multidrug-resistant subline. Oxazoline and Pd complex 1 induced apoptosis in A549 cells. DFT calculations were also performed to exhibit the excellent bioactivity of complex 1 against A549, MDA-MB-231, and KB cells. Complex 1, with the best docking score and a stable interaction network within the binding site of the G-quadruplex, could stably interact with the G-quadruplex. Additionally, complex 1 was further used in the animal experiment of human lung adenocarcinoma cells in nude mice. By comparing with the model control group, the tumour volume, relative tumour volume and relative tumour proliferation rate T/C decreased significantly in the cisplatin group and compound 1 (complex 1) group., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

HIV-1 maturation is the final step in the retroviral lifecycle that is regulated by the proteolytic cleavage of the Gag precursor protein. As a first-in-class HIV-1 maturation inhibitor (MI), bevirimat blocks virion maturation by disrupting capsid-spacer peptide 1 (CA-SP1) cleavage, which acts as the target of MIs. Previous alterations of beesioside I (1) produced (20S,24S)-15ꞵ,16ꞵ-diacetoxy-18,24; 20,24-diepoxy-9,19-cyclolanostane-3ꞵ,25-diol 3-O-3′,3′-dimethylsuccinate (3, DSC), showing similar anti-HIV potency compared to bevirimat. To ascertain the binding modes of this derivative, further modification of compound 1 was conducted. Three-dimensional quantitative structure−activity relationship (3D-QSAR) analysis combined with docking simulations and molecular dynamics (MD) were conducted. Five new derivatives were synthesized, among which compound 3b showed significant activity against HIV-1NL4-3 with an EC50 value of 0.28 µM. The developed 3D-QSAR model resulted in great predictive ability with training set (r2 = 0.99, q2 = 0.55). Molecular docking studies were complementary to the 3D-QSAR analysis, showing that DSC was differently bound to CA-SP1 with higher affinity than that of bevirimat. MD studies revealed that the complex of the ligand and the protein was stable, with root mean square deviation (RMSD) values <2.5 Å. The above results provided valuable insights into the potential of DSC as a prototype to develop new antiviral agents.

Quinoline and quinazoline alkaloids, two important classes of N-based heterocyclic compounds, have attracted scientific and popular interest worldwide since the 19th century. More than 600 compounds have been isolated from nature to date. To build on our two prior reviews, we reexamined the promising molecules described in previous reports and provided updated literature on novel quinoline and quinazoline alkaloids isolated over the past 5 years. This chapter reviews and discusses 205 molecules with a broad range of bioactivities, including antiparasitic and insecticidal, antibacterial and antifungal, cardioprotective, antiviral, anti-inflammatory, and other effects. This survey should provide new clues or possibilities for the discovery of new and better drugs from the original naturally occurring quinoline and quinazoline alkaloids., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Phenanthrene-based tylophorine-1 (PBT-1) was identified previously as a lead compound in an anticancer drug discovery effort based on natural Tylophora alkaloids. An expanded structural optimization using a new more efficient synthetic route provided 14 PBT-derivatives. Eleven compounds displayed obvious antiproliferative activities in cellular assays (GI 50 0.55-9.32 μM). The most potent compounds 9c , 9g , and 9h (GI 50 < 1 μM) contained a 7-hydroxy group on the phenanthrene B-ring in addition to a pendant piperidine E-ring with different 4-substituents. Compound 9h with NH 2 as the piperidine substituent was at least 4-fold more potent against triple-negative breast cancer MDA-MB-231 than estrogen-responsible breast cancer MCF-7 cell growth. In further biological evaluations, the new active compounds induced cell cycle accumulation in the late S and G2/M phase without interfering with microtubule formation or cell morphology. These results on the optimization of the B- and E-rings of PBT-1 should benefit further development of novel antitumor agents., Competing Interests: The authors declare no competing financial interest., (© 2021 American Chemical Society.)

Tigliane esters show many biological activities, including anti-HIV-1 activity. Our aim in this study was to establish structure-anti-HIV activity relationships for four series of tigliane-type diterpenoids. We synthesized and evaluated 29 new phorbol ester derivatives for anti-HIV activity and for cytotoxicity against human tumor cell lines. Among them, three derivatives, two phorbol-13-monoesters (5d and 5e) and a phorbol-12,13-diester (6a), showed significant anti-HIV activity. We found that better anti-HIV activity was often associated with a shorter acyl ester at C-13. Particularly, compounds with a phenyl ring in the ester side chain exhibited excellent anti-HIV activity and had good safety indexes. Due to its significant anti-HIV potency with a high selectivity index, phorbol-12,13-dicinnamoate (6a) was chosen as the potential candidate for further preclinical trials., (Copyright © 2021. Published by Elsevier Ltd.)

Structurally diverse tigliane diterpenoids have drawn significant research interest for drug discovery over many decades. Using LC-MS-guided fractionation and separation, the first phytochemical investigation on Wikstroemia lamatsoensis led to the isolation of eight tiglianes ( 1 - 8 ), including two new compounds, wikstrocin D ( 1 ) and wikstrocin E ( 2 ). The new structures were elucidated based on extensive physicochemical and spectroscopic analyses. The characteristic ESIMS/MS fragmentations of tiglianes 1 - 8 were also summarized. Among the isolated tiglianes, three compounds ( 8 , 5 , and 7 ) showed the most potent anti-HIV activity, with IC 50 values of 0.18, 3.8, and 12.8 nM, respectively.

Fourteen glaucocalyxin A biotinylated derivatives, one glaucocalyxin C biotinylated derivative, and two oridonin biotinylated derivatives were designed and synthesized. Their structures were confirmed from 1 H NMR, 13 C NMR and HRMS data. The derivatives were evaluated for cytotoxic activities against lung (A549), cervical cancer cell line HeLa derivative (KB), multidrug-resistant KB subline (KB-VIN), triple-negative breast (MDA-MB-231), and estrogen receptor-positive breast (MCF-7) cancer cell lines.[Formula: see text].

Prior modification of betulinic acid (1), a natural product lead with promising anti-HIV activity, produced 3-O-(3',3'-dimethylsuccinyl)betulinic acid (bevirimat, 3), the first-in-class HIV maturation inhibitor. After 3-resistant variants were found during Phase I and IIa clinical trials, further modification of 3 produced 4 with improved activity against wild-type and 3-resistant HIV-1. In continued efforts to optimize 1, 63 final products have now been designed, synthesized, and evaluated for anti-HIV-1 replication activity against HIV-1 NL4-3 infected MT-4 cell lines. Five known and 21 new derivatives were as or more potent than 3 (EC 50 0.065 μM), while eight new derivatives were as or more potent than 4 (EC 50 0.019 μM). These derivatives feature expanded structural diversity and chemical space that may improve the antiviral activity and address the growing resistance crisis. Structure-Activity Relationship (SAR) correlations were thoroughly analyzed, and a 3D Quantitative SAR model with high predictability was constructed to facilitate further rational design and development of new potent derivatives., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021. Published by Elsevier Masson SAS.)

Thirty-two new diosgenin derivatives were designed, synthesized, and evaluated for their cytotoxic activities in three human cancer cell lines (A549, MCF-7, and HepG2) and normal human liver cells (L02) using an MTT assay in vitro. Most compounds, especially 8 , 18 , 26 , and 30 , were more potent when compared with diosgenin. The structure-activity relationship results suggested that the presence of a succinic acid or glutaric acid linker, a piperazinyl amide terminus, and lipophilic cations are all beneficial for promoting cytotoxic activity. Notably, compound 8 displayed excellent cytotoxic activity against HepG2 cells (IC 50 = 1.9 μM) and showed relatively low toxicity against L02 cells (IC 50 = 18.6 μM), showing some selectivity between normal and tumor cells. Studies on its cellular mechanism of action showed that compound 8 induces G0/G1 cell cycle arrest and apoptosis in HepG2 cells. Predictive studies indicated that p38α mitogen-activated protein kinase (MAPK) is the optimum target of 8 based on its 3D molecular similarity, and docking studies showed that compound 8 fits well into the active site of p38α-MAPK and forms relatively strong interactions with the surrounding amino acid residues. Accordingly, compound 8 may be used as a promising lead compound for the development of new antitumor agents.

Indolizidine alkaloids are chemical constituents isolated from various marine and terrestrial plants and animals, including but not limited to trees, fungi, ants, and frogs, with a myriad of important biological activities. In this review, we discuss the biological activity and pharmacological effects of indolizidine alkaloids and offer new avenues toward the discovery of new and better drugs based on these naturally occurring compounds., (© 2020 Wiley Periodicals LLC.)

The influenza pandemic continues to threaten public health due to its high morbidity and mortality rates, despite some successes in antiviral research. Natural drugs are important alternative therapies in the treatment of and recovery from influenza and have been the subjects of intense investigation during the last few decades. Many reports have shown that the development of novel bioactive chemicals extracted from natural drugs has significant advantages. Oseltamivir is a successful case of an anti-influenza drug synthesized using two natural products, quinic acid, and shikimic acid, as starting materials. In China, traditional Chinese medicine (TCM) plays an important role in the treatment of influenza. TCM herbal extracts and prescriptions or their isolated bioactive constituents have shown significant therapeutic and preventive effects against influenza. For example, the roots of Isatis indigotica (Banlangen) fight viral infection by targeting both the virus and the host and have significantly different effects than those of synthetic chemicals. Lianhuaqingwen capsule exerts its anti-influenza activity by regulating the immune response to interfere with both viral and host reactions and might well be an alternative therapeutic option to treat influenza virus infection. This paper reviews the chemical ingredients, crude extracts, and TCM prescriptions with anti-influenza activity reported during the period of 2010-September 2019. We hope that this comprehensive review will not only fuel research on anti-influenza active natural products and TCM research but also provide a promising alternative candidate for further anti-influenza drug development., (© 2020 Wiley Periodicals LLC.)

Isoquinoline alkaloids, an important class of N-based heterocyclic compounds, have attracted considerable attention from researchers worldwide since the early 19th century. Over the past 200 years, many compounds from this class were isolated, and most of them and their analogs possess various bioactivities. In this review, we survey the updated literature on bioactive alkaloids and highlight research achievements of this alkaloid class during the period of 2014-2018. We reviewed over 400 molecules with a broad range of bioactivities, including antitumor, antidiabetic and its complications, antibacterial, antifungal, antiviral, antiparasitic, insecticidal, anti-inflammatory, antioxidant, neuroprotective, and other activities. This review should provide new indications or directions for the discovery of new and better drugs from the original naturally occurring isoquinoline alkaloids., (© 2020 Wiley Periodicals LLC.)

The human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) epidemic is one of the world's most serious health challenges. Although combination antiretroviral therapy provides effective viral suppression, current medicines used against HIV cannot completely eradicate the infectious disease and often have associated toxicities and severe side effects in addition to causing drug resistance. Therefore, the continued development of new antiviral agents with diverse structures and novel mechanisms of action remains a vital need for the management of HIV/AIDS. Natural products are an important source of drug discovery, and certain triterpenes and their analogs have demonstrated potential as pharmaceutical precursors for the treatment of HIV. Over the past decade, natural triterpenoids and analogs have been extensively studied to find new anti-HIV drugs. This review discusses the anti-HIV triterpenoids and analogs reported during the period of 2009-2019. The article includes not only a comprehensive review of the recent anti-HIV agent development from the perspective of medicinal chemistry, but also discusses structure-activity relationship analyses of the described triterpenoids., (© 2020 Wiley Periodicals LLC.)

Oxidative therapy, a strategy that specifically increases reactive oxygen species (ROS) levels in tumor cells by disrupting the redox homeostasis has gained increasing interest. The antitumor effects of the natural product piperlongumine (PL) appear to result from its ability to increase intracellular ROS levels via inhibition of antioxidative thioredoxin reductase (TrxR). Twenty-seven benzylidenecyclohexenone-based PL analogues (2a-v and 15a-e) were designed, synthesized and evaluated for their pharmacological properties. Most of the compounds exhibited potent antiproliferative activities against five human cancer cell lines, especially against breast tumor cells. One of the most promising analogueues 2c showed 12-fold higher inhibitory activity against the thioredoxin reductase (TrxR) than PL and surpressed the expression of TrxR1 protein in breast cancer cells and inhibited TrxR enzymatic activity. In addition, 2c increased ROS levels and resulted in marked apoptosis by regulating apoptosis-related proteins expressed in the breast cancer cells. Compound 2c also triggered the formation of autophagosomes and autolysosomes by promoting the expression of LC3-II and Beclin-1 and diminishing the expression of LC3-I and p62 proteins. Finally, 2c displayed low acute toxicity and good inhibitory potency to tumors in mice. Overall, 2c is a promising anti-breast cancer candidate warranting further investigation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Novel betulinic/betulonic acid-nucleoside hybrids were synthesized as possible new anti-HIV agents. Among the synthesized hybrids, two compounds were highly effective against HIV. Compared with AZT and DSB, compounds 10a (IC 50 = 0.0078 μM, CC 50 = 9.6 μM) and 10b (IC 50 = 0.020 μM, CC 50 = 23.8 μM) showed more potent or equipotent, respectively, anti-HIV activity but displayed lower cytotoxicity., Competing Interests: The authors declare no competing financial interest.

Platelet thrombosis is the main pathogeny resulting in the low curability of ischemic stroke, a leading cause of mortality and disability worldwide. Metformin, a biguanide derivative that is the first-line oral medicine for type 2 diabetes, alleviates the severity of ischemic stroke in diabetic patients and suppresses platelet activation in experimental animal model. However, the clinical implementation of commercial biguanide analogs for stroke related to platelet thrombosis remains challenging due to its weak potency, poor pharmacokinetic characteristics and possible hypoglycemia. Here, twenty-three biguanide derivatives were designed and synthesized based on the principles of bioisosteres. These derivatives were evaluated for the activity of antiplatelet thrombosis in vivo. We found that N-trifluoromethanesulfonyl biguanide derivative, compound b10, uniquely prevented cerebral infarction as well as neuronal function injury, and significantly decrease the mortality rate of ischemic stroke in the middle cerebral artery occlusion mice without significant side effects. We verified that b10 directly inhibited platelets thrombus formation and decreased the compactness of stroke thrombi. Particularly, b10 exhibited good potency to inhibit human platelet activation including platelet aggregation, adhesion, pseudopodia formation, integrin GPIIb/IIIa activation, CD62P expression and clot retraction. Meanwhile, the pharmacokinetics assessment showed that b10 had satisfying pharmacological characteristics including a longer duration and a higher oral absorption ratio than its parent compound. In addition, b10 remarkably ameliorated not only stroke related to platelet thrombosis but also carotid artery thrombus formation. It is concluded that the novel potent antiplatelet thrombotic agent derived from biguanide is a promising candidate for stroke treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

As part of continuing our research on diverse C-7 derivatives of camptothecin (CPT), 16 CPT derivatives bearing piperazinyl-thiourea chemical scaffold and different substituent groups have been designed, synthesized and evaluated in vitro for cytotoxicity against five tumor cell lines (A-549, MDA-MB-231, MCF-7, KB and KBvin). As a result, all the synthesized compounds showed promising in vitro cytotoxic activity against the five tumor cell lines tested, and were more potent than irinotecan. Importantly, compounds 13 g (IC 50 = 0.514 μM) and 13o (IC 50 = 0.275 μM) possessed similar or better antiproliferative activity against the multidrug-resistant (MDR) KBvin subline than that of topotecan (IC 50 = 0.511 μM) and merit further development as anticancer candidates for clinical trail. With these results in hand, we have a reason to conclude that incorporating piperazinyl-thiourea motifs into position-7 of camptothecin confers well cytotoxic activity against cancer cell lines, probably resulting in new anticancer drugs.

Bioassay-guided fractionation of the n-butanol extract from the branches and leaves of Reutealis trisperma resulted in the isolation of six undescribed (crotignoids L ~ Q) together with two known (12-deoxyphorbol-13-hexadecanoate and 12-deoxyphorbol-13-myristate) tigliane diterpenoids. Their structures, especially the absolute configurations, were determined from extensive spectroscopic studies, including 2D NMR spectra, CD data analysis and electronic circular dichroism (ECD) calculations. All isolates were tested for anti-HIV activity against HL4-3 virus in MT4 cells. Except for crotignoid Q, the remaining seven tigliane diterpenoids exhibited potent anti-HIV activity with IC 50 values ranging from 0.0023 to 4.03 μM., Competing Interests: Declaration of competing interest All the authors of this manuscript state that they have no conflict of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background and Purpose: Multidrug resistance (MDR) remains the main obstacle in cancer treatment and overexpression of P-glycoprotein (P-gp) is one of the most common causes of chemoresistance. The development of novel P-gp inhibitors from natural products is a prospective strategy to combat MDR cancers. Among the natural sesquiterpene compounds, sesquiterpene pyridine alkaloids exhibit various biological properties. Therefore, in the present study, we evaluated the modulatory effects of wilforine on P-gp expression and function. The molecular mechanisms and kinetic models of wilforine-mediated P-gp inhibition were further investigated., Methods: The human P-gp stable expression cells (ABCB1/Flp-In TM -293) and human cervical cancer cells (sensitive: HeLaS3; MDR: KBvin) were used. The cell viability was assessed by SRB assay. The inhibitory effect of wilforine on P-gp efflux and the underlying mechanism were evaluated by assays for calcein-AM uptake, rhodamine123 and doxorubicin efflux, ATPase activity, real-time quantitative RT-PCR, apoptosis, and cell cycle analysis. Molecular docking was performed by the docking software CDOCKER with BIOVIA Discovery Studio 4.5 (D.S. 4.5)., Results: We found that wilforine significantly inhibited the efflux activity of P-gp in a concentration-dependent manner. Further kinetic analysis demonstrated that wilforine significantly inhibited P-gp efflux function by competitive inhibition and stimulated the basal P-gp ATPase activity. In addition, wilforine re-sensitized MDR cancer cells to chemotherapeutic drugs. The docking model indicated that wilforine was bound to residues of P-gp such as LEU884, LYS887, THR176 and ASN172., Conclusion: These results suggest a novel future therapeutic strategy for MDR cancer using wilforine as an adjuvant treatment with chemotherapy., Competing Interests: Conflicts of Interest The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results., (Copyright © 2020 Elsevier GmbH. All rights reserved.)

A 3,4-dihydroisocoumarin derivative fused with dihydrothiophene, talarolactone A ( 1 ), and two known compounds, terreusinone ( 2 ) and 4,6-dihydroxy-5-methylphthalide ( 3 ), were isolated from Talaromyces sp. associated with Xanthoparmelia angustiphylla . The structure of 1 was deduced from extensive spectroscopic data, electronic circular dichroism calculations, and X-ray diffraction analyses. A plausible biosynthetic pathway of 1 was further proposed. Compound 1 showed selective antimigratory activity in a wound-healing assay without appreciable cytotoxic activity.

Seven new cucurbitane-type triterpenoids, kuguaovins A-G ( 1 - 7 ), and five known ones were isolated from the rattans of wild Momordica charantia . Their structures were established by spectroscopic data analyses, including 1D and 2D NMR, IR, and MS techniques. The absolute configurations of the cucurbitanes were determined from NOESY data and partially by X-ray crystallographic analysis. In pharmacological studies, compounds 1 - 7 and 9 - 12 exhibited weak anti-inflammatory effects (IC 50 = 15-35 μM), based on an anti-NO production assay.

The Asian plant Kalimeris shimadai has been used as food and ethnologic medicine for over a thousand years. In this study, we isolated and identified one new lignan, kalshiolin A ( 1 ), and 12 known lignans ( 2-13 ). The structures were characterized by the comprehensive analyses of spectroscopic data (HR-ESI-MS, IR, 1D, and 2D-NMR) and the absolute configuration of 1 was determined from ECD calculations. The new compound 1 was also screened for cytotoxic activity but did not show significant potency (IC 50 35.9-43.3  μ M) against A549, MDA-MB-231, MCF7, KB, and KB-VIN cell lines.

For the purpose of advancing our research on diverse C-20 decorated derivatives of camptothecin (CPT), 46 new CPT acylthiourea derivatives were synthesized and evaluated in vitro for their cytotoxicity. All the compounds showed promising in vitro cytotoxicity against six tumor cell lines (Hep3B, MCF7, A549, MDA-MB-231, KB and KB-vin). Out of them, compound c20 possesses remarkable in vitro cytotoxic activity and is more potent than topotecan. Mechanistically, c20 not only induces cell cycle arrest and cell apoptosis in A549 cells, but also inhibits Topo I activity in the cell and cell-free system in a manner similar to that of topotecan. In both xenograft and primary HCC mouse models, c20 displays significant in vivo anti-cancer activity and is more potent than topotecan. In addition, the acute toxicity assay showed that c20 has no apparent toxicity to mouse liver, kidney and hemopoietic system of the FVB/N mice. Take together, these results indicated that compound c20 could be a potential anti-cancer candidate for further clinical trial., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Daphnane diterpenes with a 5/7/6-tricyclic ring system exhibit potent anti-HIV activity but are found in low abundance as plant natural products. In this study, an effective approach based on mass spectrometric fragmentation pathways was conducted to specifically recognize and isolate anti-HIV compounds of this type from Daphne genkwa . Briefly, the fragmentation pathways of reference analogues were elucidated based on characteristic ion fragments of m / z 323 → 295 → 267 or m / z 253 → 238 → 197 by ultra-high-performance liquid chromatography-ion trap tandem mass spectrometry (UPLC-IT-MS n ) and then applied to the differentiations of substances with or without an oxygenated group at C-12. Twenty-seven daphnane diterpenes were successfully recognized from a petroleum ether extract of D. genkwa , including some potential new compounds and isomers that could not be identified accurately only from the ion fragments. Further separation of these target compounds using high-speed countercurrent chromatography (HSCCC) and preparative HPLC led to the isolation of three new ( 11 , 25 , and 27 ) and 14 known compounds, whose structures were identified and confirmed based on MS, NMR, and electronic circular dichroism (ECD) spectroscopy. The isolates exhibited anti-HIV activities at nanomolar concentrations. The results demonstrated that this strategy is feasible and reliable to rapidly recognize and isolate daphnane diterpenes from D. genkwa .

Scaffold hopping-driven lead optimizations were performed based on our prior lead 7-methoxy-4-(2-methylquinazolin-4-yl)-3,4-dihydroquinoxalin-2(1 H )-one ( 2a ) by C-ring expansion and isometric replacement of the A/B-ring, successively, aimed at finding new potential alternative drug candidates with different scaffold(s), high antitumor activity, and other improved properties to replace prior, once promising drug candidates that failed in further studies. Two series of new compounds 7 ( a-d ) and 13 ( a-j ) were synthesized and evaluated for antitumor activity, leading to the discovery of three highly potent compounds 13c , 13d , and 13e with different scaffolds. They exhibited similar high antitumor activity with single digital low nanomolar GI 50 values (4.6-9.6 nM) in cellular assays, comparable to lead 2a , clinical drug candidate CA-4, and paclitaxel in the same assays. Further biological evaluations identified new active compounds as tubulin polymerization inhibitors targeting the colchicine binding site. Moreover, 13d showed better aqueous solubility than 2a and a similar log P value., Competing Interests: The authors declare no competing financial interest., (Copyright © 2019 American Chemical Society.)

In a study of the potential anti-inflammatory constituents from Kalimeris shimadae , six new sesquiterpenes, kalshinoids A-F ( 1 - 6 ), together with 21 known compounds ( 7 - 27 ), were isolated. The structures and absolute configurations of the new compounds were discerned from extensive spectroscopic analysis, and the absolute configurations of kalshinoids A, B, E, and F were established by ECD calculations. Furthermore, the identified compounds were tested for anti-inflammatory activity as assessed by inhibition of tumor necrosis factor-alpha (TNF-α) in THP-1 cells. Three sesquiterpenes [kalshinoid F, 4(15)-eudesmen-1β,7,11-triol, and 4α,10α,11-trihydroxy-1β H ,5β H -guai-7(8)-ene] reduced levels of TNF-α in lipopolysaccharide-stimulated THP-1 cells in a concentration-dependent manner and were more potent than dexamethasone. These natural sesquiterpenes merit further investigation as possible anti-inflammatory agents.

Two new carbazole alkaloids ( 1 , 2 ) and six known carbazole alkaloids ( 3 - 8 ) were isolated from Clausena anisum-olens . Their structures were elucidated based on extensive spectroscopic analysis. All isolated compounds ( 1 - 8 ) were evaluated for their anti-HIV effects on virus replication in MT-4 lymphocytes infected by HIV-1 NL4-3 Nanoluc-sec virus, and new carbazole alkaloid 1 exhibited anti-HIV activity with an EC 50 value of 2.4 μg/mL and SI of 7.1.

Natural triterpenoids, such as oleanolic acid (OA) and hederagenin, display anti-lung cancer effects, and nitric oxide (NO) is associated with some oncogenic signaling pathways. Accordingly, 17 OA/hederagenin-NO donor hybrids were designed, synthesized, and evaluated against tumor cells. The most potent compound, 13 , significantly inhibited the proliferation of five tumor cell lines (IC 50 4.6-5.2 μM), while hederagenin inhibited the growth of only A549 tumor cells (IC 50 > 10 μM). Furthermore, compound 13 showed stronger inhibitory effects on EGFR-LTC kinase activity (IC 50 0.01 μM) than hederagenin (IC 50 > 20 μM) and inhibited the proliferation of gefitinib-resistant H1975 (IC 50 8.1 μM) and osimertinib-resistant H1975-LTC (IC 50 7.6 μM) non-small-cell lung cancer (NSCLC) cells. Moreover, compound 13 produced the most NO in H1975 tumor cells, which indicated that NO may play a synergistic role. Collectively, compound 13 , a novel hederagenin-NO donor hybrid with a different chemical structure from those of the current FDA-approved EGFR-targeted anti-NSCLC drugs, may be a promising lead compound for the treatment of NSCLC expressing gefitinib-resistant EGFR with a T790 M mutation or osimertinib-resistant EGFR-LTC with an L858R/T790M/C797S mutation. This work should shed light on the discovery of new anti-NSCLC drugs targeting EGFR from natural products.

Timosaponin B III is a major bioactive steroidal saponin isolated from Anemarrhena asphodeloides Bge. To potentially discover derivatives with better biological activity, timosaponin B III was structurally modified via acid hydrolysis to yield one new ( 2 , timopregnane A I) C 21 steroidal glycoside and seven known compounds. Their structures were elucidated on the basis of NMR spectroscopy and mass spectrometry. All eight compounds were evaluated for cytotoxic activity against MCF7, SW480, HepG2, and SGC7901 cell lines in vitro . As a result, compounds 6 and 7 showed significant activity (IC 50 2.94-12.2 μM) against all tested cell lines. Structure-activity relationships of these compounds were investigated and the preliminary conclusions were provided. Moreover, a new transformation pathway was discovered in the acid hydrolysis of timosaponin B III for the first time.

Multidrug resistance presents an obstacle in cancer treatment. Among numerous combative strategies, collateral sensitivity (CS) drugs have opened a new avenue to defeat cancer by exploiting selective toxicity against multidrug-resistant (MDR) cancer. In the present study, a clinically used synthetic steroid hormone, danazol, was investigated for its CS properties and cytotoxic mechanisms. Compared with natural hormones, danazol possessed a stronger selective cytotoxicity against MDR cancer cells. Danazol induced the arrest of MDR cancer cells at the G2/M phase and caspase-8-related early apoptosis. Furthermore, in MDR cancer cells, danazol reduced STAT3 phosphorylation as well as the expression of STAT3-regulated genes involved in cell survival, such as c-Myc, CDC25, and CDK1. Danazol also upregulated the cell cycle inhibitor p21 in MDR cancer cells. Supporting the experimental results, docking studies have revealed that danazol can likely bind favourably with STAT3. Taken together, our results suggest that danazol exerts a CS effect by inhibiting the STAT3 pathway in MDR cancer cells and thus provides a possible solution for MDR cancers.

Currently, due to the HIV latency mechanism, the search continues for effective drugs to combat this issue and provide a cure for AIDS. Gnidimacrin activates latent HIV-1 replication and inhibits HIV-1 infection at picomolar concentrations. This natural diterpene was able to markedly reduce the latent HIV-1 DNA level and the frequency of latently infected cells. Therefore, gnidimacrin is an excellent lead compound, and its anti-HIV potential merits further investigation. Twenty-nine modified gnidimacrin derivatives were synthesized and evaluated in assays for HIV replication and latency activation to establish which molecular structures must be maintained and which can tolerate changes that may be needed for better pharmacological properties. The results indicated that hydroxyl substituents at C-5 and C-20 are essential, while derivatives modified at 3-OH with aromatic esters retain anti-HIV replication and latent activation activities. The half-lives of the potent GM derivatives are over 20 h, which implies that they are stable in the plasm even though they contain ester linkages. The established structure-activity relationship should be useful in the development of gnidimacrin or structurally related compounds as clinical trial candidates.

Betulinic acid (BA), a pentacyclic triterpenoid, exhibits broad spectrum antiproliferative activity, but generally with only modest potency. To improve BA's pharmacological properties, fluorine was introduced as a single atom at C-2, creating two diastereomers, or in a trifluoromethyl group at C-3. We evaluated the impact of these groups on antiproliferative activity against five human tumor cell lines. A racemic 2-F-BA (compound 6) showed significantly improved antiproliferative activity, while each diastereomer exhibited similar effects. We also demonstrated that 2-F-BA is a topoisomerase (Topo) I and IIα dual inhibitor in cell-based and cell-free assays. A hypothetical mode of binding to the Topo I-DNA suggested a difference between the hydrogen bonding of BA and 2-F-BA to DNA, which may account for the difference in bioactivity against Topo I., (Copyright © 2019. Published by Elsevier Ltd.)

Six new dammarane-type saponins, gypenosides CP1-6 ( 1 6 ), along with 19 known compounds 7 ⁻ 25 , were isolated and characterized from the aerial parts of Gynostemma pentaphyllum . Among these compounds, eight dammarane-type saponins, 2 , 5 , 6 , 7 , 11 , 12 , 13 , and 15 , exhibited the greatest antiproliferative effects against two human tumor cell lines (A549 and HepG2)., Competing Interests: The authors declare no conflict of interest.

Monoterpenoid indole alkaloids are structurally diverse natural products found in plants of the family Apocynaceae. Among them, vincristine and its derivatives are well known for their anticancer activity. Bousigonia mekongensis , a species in this family, contains various monoterpenoid indole alkaloids. In the current study, fourteen known aspidosperma-type monoterpenoid indole alkaloids ( 1 ⁻ 14 ) were isolated and identified from a methanol extract of the twigs and leaves of B. mekongensis for the first time. Among them, compounds 3 , 6 , 9 , and 13 exhibited similar antiproliferative activity spectra against A549, KB, and multidrug-resistant (MDR) KB subline KB-VIN cells with IC 50 values ranging from 0.5⁻0.9 μM. The above alkaloids efficiently induced cell cycle arrest at the G2/M phase by inhibiting tubulin polymerization as well as mitotic bipolar spindle formation. Computer modeling studies indicated that compound 7 likely forms a hydrogen bond (H-bond) with α- or β-tubulin at the colchicine site. Evaluation of the antiproliferative effects and SAR analysis suggested that a 14,15-double bond or 3α-acetonyl group is critical for enhanced antiproliferative activity. Mechanism of action studies demonstrated for the first time that compounds 3 , 4 , 6 , 7 , and 13 efficiently induce cell cycle arrest at G2/M by inhibiting tubulin polymerization by binding to the colchicine site.

In this study, 12 known cycloartane triterpenoids (1-12) with four different skeletons isolated from the roots of Souliea vaginata were screened for the first time for in vitro anti-HIV activity using AZT as a standard. Among the compounds, beesioside I (1) showed the highest potency against HIV-1 NL4-3 with an EC 50 value of 2.32 μM (CC 50  > 40 μM). Preliminary structure-activity relationship (SAR) studies on 1 indicated that simple modification of its aglycone (13) could significantly influence the antiviral activity. Particularly, the introduction of an acyl group at the C-3 position of 13 led to significant improvement in both anti-HIV potency and selectivity index. Among all synthetically modified derivatives, compound 13g was the most potent compound with an EC 50 value of 0.025 μM and TI value greater than 800, comparable to those of 3-O-(3',3'-dimethylsuccinyl)-betulinic acid (DSB, bevirimat). Other analogues exhibited strong to weak inhibition of HIV-1 replication in MT-4 cells. The length, carboxylic terminus, and C-3' dimethyl substitution of the C-3 side chain substantially affected the anti-HIV activity. Finally, compound 13g was an effective agent against HIV with high potential for further investigation., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Background: Multidrug resistance (MDR) in cancer is one of the main obstacles in treatment with chemotherapy. Drug efflux through P-glycoprotein is the major mechanism involved in MDR. A potential strategy to provide the best possible clinical outcomes is to develop P-glycoprotein (P-gp) inhibitors from natural products., Purpose: The present study investigated the effects of the natural sesquiterpene lactone tenulin and its derivative isotenulin on human P-gp; the mechanisms of kinetic interactions were also explored., Methods: The human P-gp (ABCB1/Flp-In™-293) stable expression cells were established by using the Flp-In™ system. The effects of tenulin and isotenulin on cell viability were evaluated by SRB assays in established cell lines, sensitive cancer cell line (HeLaS3), and resistant cancer cell line (KB-vin). The transporter inhibition ability was evaluated by calcein-AM uptake assays. The P-gp inhibition kinetics of tenulin and isotenulin were evaluated by rhodamine123 and doxorubicin efflux assays. The ATPase activity was evaluated with the Pgp-Glo™ Assay System., Results: Tenulin and isotenulin significantly inhibited the P-gp efflux function by stimulating P-gp ATPase activity. Tenulin and isotenulin interacted with the effluxes of rhodamine 123 and doxorubicin through a competitive and noncompetitive mechanism, respectively. The combinations of tenulin and isotenulin with chemotherapeutic drugs significantly resensitized MDR cancer cells., Conclusion: These results suggested that tenulin and isotenulin are potential candidates to be developed for synergistic treatment of MDR cancers., (Copyright © 2018 Elsevier GmbH. All rights reserved.)

Ethnopharmacological Relevance: The edible plant Physalis alkekengi (PA) is used in traditional medicine to treat diabetes. However, the anti-diabetic effects and constituents of the fruit and aerial parts of this plant have not been studied extensively., Aim of the Study: The purpose of this study was to investigate the antidiabetic potential of Physalis alkekengi and identify its chemical constituents., Materials and Methods: In the present study, the in vitro glucose uptake capacity was tested using the 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-d-glucose (2-NBDG) assay in HepG2 cells. Secondly, the anti-diabetes effects of the ethyl acetate extracts of the aerial parts/fruit (EAP/EAF) of P. alkekengi were evaluated in high-fat diet-fed and streptozotocin-induced diabetic rats (seven groups, n = 7) daily at doses of 300 and 600 mg/kg for 28 days. Fasting blood glucose (FBG) was measured with a glucometer and the levels of total cholesterol (TC), triglyceride (TG), glycated serum protein (GSP), and fasting insulin (FINS) were measured by ELISA. Furthermore, insulin sensitivity index (ISI) and homeostasis model assessment-insulin resistance index (HOMA-IR) were calculated based on FBG and FINS. Changes in blood glucose concentration were assessed after an oral glucose challenge in diabetic rats treated with EAF and EAP extracts. In all assays, rosiglitazone, a current antidiabetic drug and insulin sensitizer, was also tested. Finally, the compounds in EAP were identified by HPLC-ESI-QTOF-MS analysis., Results: EAP increased the uptake of 2-NBDG, a measure of direct glucose uptake, in HepG2 cells. Next, in diabetic rats treated with P. alkegenki extracts for 28 days, the levels of FBG, TC, TG and GSP and were lowered effectively, while FINS was increased significantly. EAP/EAF enhanced insulin sensitivity significantly as measured by ISI and HOMA-IR along with oral glucose tolerance test analysis. The EAP generally exerted the greatest effects. Lastly, a HPLC-ESI-Q-TOF-MS analysis identified 50 compounds, including 26 physalins, 10 flavonoids, and 9 phenolic acids, with 21 compounds found for the first time in P. alkekengi., Conclusions: The results support the merit of P. alkekengi as an antidiabetic herbal medicine or dietary supplement., (Copyright © 2018 Elsevier B.V. All rights reserved.)

To follow-up on our prior Part I review, this Part II review summarizes and provides updated literature on novel quinoline and quinazoline alkaloids isolated during the period of 2009-2016, together with the biological activity and the mechanisms of action of these classes of natural products. Over 200 molecules with a broad range of biological activities, including antitumor, antiparasitic and insecticidal, antibacterial and antifungal, cardioprotective, antiviral, anti-inflammatory, hepatoprotective, antioxidant, anti-asthma, antitussive, and other activities, are discussed. This survey should provide new clues or possibilities for the discovery of new and better drugs from the original naturally occurring quinoline and quinazoline alkaloids., (© 2018 Wiley Periodicals, Inc.)

The aim of this study was to develop a new drug substance with low toxicity and effective inhibitory activity against cisplatin-resistant oral cancer. The naturally produced pterostilbene was selected as the lead compound for design and synthesis of a series of bis(hydroxymethyl)propionate-based prodrugs. All derivatives were screened for antiproliferative effects against the cisplatin-resistant oral squamous (CAR) cell line and the results indicated that several compounds demonstrated superior inhibitory activity compared with pterostilbene and resveratrol. Among them, the most promising compound, 12, was evaluated for in vivo antitumor activity in a CAR xenograft nude mouse model. Obvious antitumor activity was observed at the lowest oral dose (25 mg/kg/day). Increasing the dose of 12 to 100 mg/kg/day reduced the tumor size to 22% of the control group. Based on these findings as well as the extremely low toxicity seen in the in vivo studies, we believe that compound 12 could serve as a new lead for further development., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Euphorbia kansui showed potent anti-HIV-1 activity during screening of a library composed of plant extracts from Euphorbiaceae and Thymelaeaceae families. Bioassay-guided isolation led to identification of ingenane esters as the active compounds. Further chemical modification resulted in 3-(2-naphthoyl)ingenol (23), which exhibited the most potent anti-HIV-1 activity. Compound 23 also acted as an HIV-1-latency-reversing agent on activation of HIV-1 replication in a latently infected U1 cell model and a T cell latent HIV-1 model JLat-A2., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Swietenia is a genus in the plant family Meliaceae. This genus contains seven to eight known species, found in the tropical and subtropical regions of the Americas and West Africa. Thus far, more than 160 limonoids have been isolated from four species of the genus Swietenia . Limonoids are rich in structure type and biological activity, and these compounds are the main active components in the Swietenia species. This paper will give a comprehensive overview of the recent phytochemical and pharmacological research on the terpenes from Swietenia plants and encourage further drug discovery research.

Fourteen novel amino-quinoline-5,8-dione derivatives (6a-h and 7a-h) were designed and synthesized by coupling different alkyl- or aryl-amino fragments at the C6- or C7-position of quinoline-5,8-dione. All target compounds showed antiproliferative potency in the low micromolar range in both drug sensitive HeLaS3 and multidrug resistant KB-vin cell lines. Compounds 6h, 6d, 7a, and 7d exhibited more potent antiproliferative effects than the other compounds. Especially, compounds 6d and 7d displayed NQO1-dependent cytotoxicity and competitive NQO1 inhibitory effects in both drug sensitive HeLaS3 and multidrug resistant KB-vin cell lines. Furthermore, compounds 6h, 6d, 7a, and 7d induced a dose-dependent lethal mitochondrial dysfunction in both drug sensitive HeLaS3 and multidrug resistant KB-vin cells by increasing intracellular reactive oxygen species (ROS) levels. Notably, compound 7d selectively inhibited cancer cells, but not non-tumor liver cell proliferation in vitro, and significantly triggered HeLaS3 cell apoptosis by regulating apoptotic proteins of Bcl-2, Bax, and cleaved caspase-3 in a dose-dependent manner. Our findings suggest that these novel C6- or C7-substituted amino-quinoline-5,8-dione derivatives, such as 7d, could be further developed in the future as potent and selective antitumor agents to potentially circumvent multi-drug resistance (MDR)., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

The aims of the present study were to assess the anti-diabetic effects of Physalis alkekengi L. (PA) in 3T3-L1 pre-adipocyte cells and HepG2-GFP-CYP2E1 (E47) cells and in a pre-diabetic rat model, as well as to identify the active chemical constituents. The in vitro results showed that PA has a strong anti-diabetic capacity to relieve oxidative stress and inhibit α-glucosidase activity. Mechanistic analysis also showed that ethyl acetate extracts of aerial parts and fruit of PA (PAG-EA and PAF-EA) enhanced glucose transporter 4 expression and function as well as enhanced insulin sensitivity by inhibiting the expression of cytochrome P450-2E1 (CYP2E1) mRNA and protein. In vivo, PAG-EA and PAF-EA significantly decreased the levels of fasting blood glucose and fasting insulin, as well as total cholesterol and triglyceride, in the pre-diabetic rats. The results from insulin sensitivity index and homeostasis model assessment-insulin resistance index along with an oral glucose tolerance test also showed that PAG-EA and PAF-EA could significantly enhance the insulin sensitivity, which confirmed the in vitro findings. Moreover, HPLC-ESI-QTOF-MS analysis identified flavonoids, physalins and phenolic acids as the main plant constituents. Our findings support the ethnopharmacological use of PA fruit, along with its aerial parts, as a strong anti-diabetic agent. The EA fraction, especially the constituent polyphenols and flavonoids, may have a good potential to treat diabetes., (Copyright © 2018 Elsevier B.V. All rights reserved.)