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As angiogenesis plays a pivotal role in tumor progression and metastasis, leading to more cancer-related deaths, the angiogenic process can be considered as a target for diagnostic and therapeutic applications. The vascular endothelial growth factor receptor-1 (VEGR-1) and VEGFR-2 have high expression on breast cancer cells and contribute to angiogenesis and tumor development. Thus, early diagnosis through VEGFR-1/2 detection is an excellent strategy that can significantly increase a patient’s chance of survival. In this study, the VEGFR1/2-targeting peptide VGB3 was conjugated with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), using 6-aminohexanoic acid (Ahx) as a spacer to prevent steric hindrance in binding. DOTA-Ahx-VGB3 was radiolabeled with Gallium-68 (68Ga) efficiently. An in vitro cell binding assay was assessed in the 4T1 cell line. The tumor-targeting potential of [68Ga]Ga-DOTA-Ahx-VGB3 was conducted for 4T1 tumor-bearing mice. Consequently, high radiochemical purity [68Ga]Ga-DOTA-Ahx-VGB3 (RCP = 98%) was prepared and stabilized in different buffer systems. Approximately 17% of the radiopeptide was internalized after 2 h incubation and receptor binding as characterized by the IC50 value being about 867 nM. The biodistribution and PET/CT studies revealed that [68Ga]Ga-DOTA-Ahx-VGB3 reached the tumor site and was excreted rapidly by the renal system. These features convey [68Ga]Ga-DOTA-Ahx-VGB3 as a suitable agent for the noninvasive visualization of VEGFR-1/2 expression.

Abstract Kisspeptin (kp) is a key regulator of reproduction, which stimulates sexual maturation and gametogenesis in mammals, amphibians, and teleosts. In the present study, to enhance the biological activity of kp10, a novel analog (referred to as M-kp10) was designed based on the endogenous goldfish variant, in which phenylalanine 6 was substituted by tryptophan and the N-terminus was acetylated. Compared with the native kp-10 and salmon gonadotropin-releasing hormone (GnRH3), the effect of M-kp10 on sexual hormones and reproductive indices as well as the expression of kiss1, cyp19a1, and kiss1ra genes in goldfish (Carassius auratus) was investigated. In practice, peptides were synthesized based on the standard Fmoc-solid-phase peptide synthesis and purified by employing RP-HPLC, followed by approving their structure using ESI-MS. The results showed that M-kp10 increased significantly 17,20β-DHP, LH, FSH and E2 as well as fecundity, hatching and fertilization percentages than the other peptides. Histological studies revealed that M-kp10 led to the faster growth of ovarian follicles compared to the kp-10 and GnRH3. The genes of cyp19a1, kiss1ra, and kiss1 were remarkably more expressed after treatment with M-kp10. In conclusion, the results indicated the superiority of M-kp10 over kp-10 in inducing sexual maturation and accelerating the percentage of fecundity, suggesting that M-kp10 could be a promising candidate for application in the artificial breeding of fish.

Abstract This manuscript reports an impressive and facile strategy for synthesizing isoxazole derivatives using immobilized Cu (I) in metformin-functionalized β-cyclodextrin as a catalyst. The architecture of this catalyst was characterized by different analytical techniques such as Fourier transform infrared spectroscopy, Thermogravimetric analysis, X-ray diffraction, Field emission scanning electron microscopy, and Energy-dispersive X-ray spectroscopy. The catalyst showed remarkable reusability even after 7 consecutive runs.

We describe a novel, simple, robust, and efficient cyclization/deoxygenation approach for the synthesis of functionalized isoquinoline derivatives. Over the course of continued studies on o-alkynylbenzaldoxime cyclization reactions, the formation of cyclic nitrones through 6-endo-dig cyclization was achieved using silver triflate or bromine as an electrophile, and subsequently, the deoxygenation process was carried out in the presence of CS2 in good to high yields.

Vascular endothelial growth factor receptor 2 (VEGFR2) mediates VEGFA signaling mainly through the PI3K/AKT/mTOR and PLCγ/ERK1/2 pathways. Here we unveil a peptidomimetic (VGB3) based on the interaction between VEGFB and VEGFR1 that unexpectedly binds and neutralizes VEGFR2. Investigation of the cyclic and linear structures of VGB3 (named C-VGB3 and L-VGB3, respectively) using receptor binding and cell proliferation assays, molecular docking, and evaluation of antiangiogenic and antitumor activities in the 4T1 mouse mammary carcinoma tumor (MCT) model showed that loop formation is essential for peptide functionality. C-VGB3 inhibited proliferation and tubulogenesis of human umbilical vein endothelial cells (HUVECs), accounting for the abrogation of VEGFR2, p-VEGFR2 and, subsequently, PI3K/AKT/mTOR and PLCγ/ERK1/2 pathways. In 4T1 MCT cells, C-VGB3 inhibited cell proliferation, VEGFR2 expression and phosphorylation, the PI3K/AKT/mTOR pathway, FAK/Paxillin, and the epithelial-to-mesenchymal transition cascade. The apoptotic effects of C-VGB3 on HUVE and 4T1 MCT cells were inferred from annexin-PI and TUNEL staining and activation of P53, caspase-3, caspase-7, and PARP1, which mechanistically occurred through the intrinsic pathway mediated by Bcl2 family members, cytochrome c, Apaf-1 and caspase-9, and extrinsic pathway via death receptors and caspase-8. These data indicate that binding regions shared by VEGF family members may be important in developing novel pan-VEGFR inhibitors that are highly relevant in the pathogenesis of angiogenesis-related diseases.

Ruthenium complexes are remarkable catalysts for the C–H activation approaches and organic transformations. Combining a Ru-catalyst with oxidants and other additives in a one-pot process is considered a sustainable approach due to the reduction in reaction steps and the minimal usage of solvents during synthesis, work-up, isolation of chemicals, and purification of the products. This review highlights the ruthenium-catalyzed organic transformations in a one-pot manner to achieve heterocyclic backbones, including indoles, benzofurans, indazoles, pyrans, pyrimidines, quinolines, and isoquinolines.

A chemically diverse set of 13 5-nitrofuran-tagged heterocyclic compounds has been prepared via the Groebke–Blackburn–Bienaymé multicomponent reaction. The testing of these compounds against the so-called ESKAPE panel of pathogens identified an apparent lead compound—N-cyclohexyl-2-(5-nitrofuran-2-yl)imidazo[1,2-a]pyridine-3-amine (4a)—which showed an excellent profile against Enterobacter cloacae, Staphylococcus aureus, Klebsiella pneumoniae, and Enterococcus faecalis (MIC 0.25, 0.06, 0.25 and 0.25 µg/mL, respectively). Its antibacterial profile and practically convenient synthesis warrant further pre-clinical development. Certain structure-activity relationships were established in the course of this study which were rationalized by the flexible docking experiments in silico. The assessment of antitubercular potential of the compounds synthesized against drug sensitive H37v strain of Mycobacterium tuberculosis revealed little potential of the imidazo-fused products of the Groebke–Blackburn–Bienaymé multicomponent reaction as chemotherapeutic agents against this pathogen.

An efficient approach for the synthesis of pyrazolopyridines containing the aminochromane motif through a base-catalyzed cyclization reaction is reported. The synthesis was carried out through a three-component reaction of (arylhydrazono)methyl-4H-chromen-4-one, malononitrile, primary amines in the presence of Et3N at room temperature. However, carrying out the reaction under the same conditions without base led to a fused chromanyl-cyanopyridine. High selectivity, high atom economy, and good to high yields in addition to mild reaction conditions are the advantages of this approach.

Abstract Biologically attractive azaspiro[4.5]trienones have been prepared via Ugi four-component reaction (Ugi-4CR) followed by bromine-mediated ipso-cyclization. This allows a straightforward synthetic route to a diverse collection of fully functionalized 3-bromoaza­spiro[4,5]trienones in moderate to good yields that can be used as templates for further modifications.

Background: The radionuclide of choice for routine clinical PET imaging is 18-F. As direct fluorination of peptides with 18-F is not possible, indirect methods using fluorinated prosthetic groups have been developed. Due to the availability of 18FDG in most PET centers, there is potential for 18FDG as a fluorinated prosthetic group. In this study, the linear peptide GPRPILE with an aminooxy group was designed, synthesized and radiolabeled with 18FDG as fibrin imaging agent. Material and Methods: Docking studies were conducted done using AutoDock 4.1 and HEX software programs. Aoe-GPRPILE peptide was designed, synthesized through Fmoc method and radiolabeled with 18FDG. The radiochemical purity, stability of radiolabeled and cold peptide in PBS and human plasma was determined using chromatographic methods. The solubility ratio of the radiolabeled peptide in lipid to water (LogP) was determined. Results: Docking and pharmacophore studies using HEX software revealed high affinity of designed peptide to fibrin (E Total=-0.01). The identity and structure of peptide were determined by LC-Mass. Peptide was stable over 24 hr in human plasma and PBS buffer. The optimum conditions of radiolabeling were 0.2 mg peptide, 1 mCi 18FDG, 90°C for 30 min, pH=5. The radiochemical purity was over 95%. The stability of radiolabeled peptide in human plasma for 2 hr was over 95%. The partition coefficient (LogP) was 1.5. Conclusion: 18FDG has a high potential to be used as a prosthetic group for radiolabeling of peptides with 18-F. In this study, peptide Aoe-GPRPILE with aminooxy was synthesized and labeled with 18FDG with high yield and radiochemical purity. Aminooxy is conjugated to peptide sequence as a prosthetic group in the last step with minimal effect on peptide properties and selectively forms stable oxime bond with the aldehyde group of 18FDG.

Background: Somatic ACE is a two-domain protein, C and N which are resulted from gene duplication. Presence of two active sites with particular properties, demonstrates functional significance of each domain. Increased levels of circulating N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), could be the result of ACE N-domain selective inhibition. Moreover, ACE C-domain specific inhibitors are able to inactivate bradykinin and inhibit the conversion of angiotensin I to angiotensin II in order to regulate blood pressure as well as reduced side effect profiles. Methods: The present study was designed to determine ACE domain specificity of the novel ACE inhibitor, onopordia which was recently isolated from Onopordon acanthium L. The ACE inhibition activity was determined using Abz-SDK (Dnp)P-OH and Abz-LFK(Dnp)-OH as ACE domain selective substrates. IC50 values of onopordia determined and compared with those of captopril as the standard. Results: IC50 values of onopordia for ACE N and C- domains were 180 µM and 244 µM respectively which demonstrated approximately similar affinity of the mentioned compound to ACE C and N-domains. A pharmacophore model was further generated based on onopordia interactions with the relevant ACE domain active sites. Conclusion: According to onopordia interactions in the ACE C and N-domain active sits, it is a potential to generate more potent and also specific inhibitor based on this new scaffold by doing accurate adjustments. Therefore, this study provides the molecular basis for further designing ACE inhibitors, which are new therapeutics in combating tissue fibrosis diseases.

Abstract Synthesis of functionalized 2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one from a cascade reaction between 3-formylchromone, malononitrile, diammonium hydrogen phosphate, and aromatic aldehydes in aqueous media is described.

Introduction: Auristatin and its derivatives (synthetic analogues of dolastatin 10, an antineoplastic natural product), are highly potent antimitotic agents which have attracted considerable attention because of their cytotoxic activity when targeting tumor cells in the form of antibody-drug conjugates (ADCs). Some sophisticated and expensive equipment such as HPLC are needed for drug/linker isolation. The aim of this study was to provide a simple aqueous work-up procedure for the isolation of such drug/linker constructs. The anti-tumor activity of the extracted drug/linker was also investigated against SKBR3 and HEK293 cancer cell lines, and cell viability was assessed. Methods: In the present study, monomethyl auristatin E (MMAE), a derivative of the cytotoxic tubulin modifier auristatin E, was covalently coupled to maleimidocaproyl-valine-citrulline-p-aminobenzoyloxycarbonyl (MC-vc-PAB), a cathepsin-B-cleavable linker, to obtain MC-vc-PAB-MMAE (vc-MMAE). Afterwards, a non-chromatographic isolation procedure was developed to isolate the drug/linker (vc-MMAE) construct. Silica gel thin-layer chromatography and electrospray ionization mass spectrometry were used to monitor the isolation procedure and to confirm the coupling of the linker to the drug, respectively. Further, the anti-tumor activity of the extracted drug/linker was investigated against SKBR3 and HEK293 cancer cell lines, and cell viability was assessed. Results: After coupling, the isolation process was confirmed as a single spot on the TLC plate. The isolation yield was calculated to be 65%. [M + H]+, [M + 2Na]+ and [M + ACN + 2H]+ species were observed in the mass spectra, showing that the coupling of MMAE to the linker is not adversely affected by the workup method. Our data revealed that the isolated vc-MMAE was highly potent against tumor cell lines, exhibiting that the workup procedure did not affect MMAE-mediated cytotoxicity. Conclusion: The isolation method described in this study can be applied for the development of a wide variety of ADCs.

Background: Monomethyl auristatin E (MMAE) is a synthetic analog of dolastatin 10, a compound originally isolated from the marine mollusk. MMAE, as a highly potent microtubule inhibitor, exerts its potent cytotoxic effect by inhibiting microtubule assembly, tubulin-dependent GTP hydrolysis and microtubes polymerization. This molecule, by itself, lacks the tumor specificity required to elicit therapeutic benefit. Nevertheless, the extremely cytotoxic potential of MMAE could be harnessed in the form of MMAE-antibody conjugates. The aim of the present study was to evaluate the cytotoxic activity of MMAE against breast (SKBR3) and kidney (HEK293) cancer cell lines in an in vitro cell-based assay.Materials and Methods: SKBR3 and HEK293 cells were treated with different concentrations ranging from 0.002048, 0.01024, 0.0512, 0.256, 1.28, 6.4, 32, 160, 800 and 4000 nM of MMAE, and cell viability was determined after 72 hours using an MTT colorimetric assay. The effect of MMAE was regularly monitored by direct observation using an invert microscope.Results: Microscopic observation showed that there was a concentration-dependent increase in cell death. Results from the MTT assay revealed a statistically significant loss of viability (PConclusion: MMAE was able to significantly inhibit cell growth at nanomolar concentrations, emphasizing its great potential for the development of antibody-drug conjugates.

Background: Breast cancer is a heterogeneous disease characterized by differential responses to targeted and chemotherapeutic agents. Antibody-drug conjugates are one of the promising strategies for the treatment of breast cancer. Monomethyl auristatin E (MMAE) is a highly potent microtubule inhibitor and a common payload used for development of antibody-drug conjugates. The purpose of this study was to investigate the cytotoxic effects of MMAE on breast cancer cell lines.Materials and Methods: MDA-MB-468 and MDA-MB-453 cells were treated with MMAE at various concentrations (1, 10, 100, and 1000 ng/ml), and cytotoxicity was measured after 48 and 72 hours using an MTT assay.Results: Our findings indicated that MMAE possesses dose- and time-dependent cytotoxic activities against human breast cancer cells. The morphological features of the treated cells were supportive of the cytotoxic activity of MMAE. The results of the MTT assay showed that MMAE has a significant cytotoxicity against MDA-MB-468 and, to a lesser degree, MDA-MB-453 cells.Conclusion: MMAE can be used as a highly cytotoxic payload for development of antibody-drug conjugates against breast cancer.

Context: Curcumin, a naturally occurring polyphenol, has been extensively studied for its broad-spectrum anticancer effects. The potential benefits are, however, limited due to its poor water solubility and rapid degradation which result in low bioavailability on administration. Objectives: This study encapsulates curcumin in nanoliposomes including an integrin-homing peptide combined with a C end R neuropilin-1 targeting motif for targeted delivery and receptor-mediated internalization, respectively. Materials and methods: The linear GHHNGR (Glycine–Histidine–Histidine–Asparagine–Glycine–Arginine) was synthesized through F-moc chemistry on 2-chlorotrityl chloride resin and conjugated to oleic acid. The lipoyl-peptide units were then co-assembled with lecithin and 0–75 mole % Tween-80 into liposomes. Curcumin was passively entrapped using a film hydration technique and its degradation profile was examined within seven consecutive days. The cytotoxic effects of the curcumin-loaded liposomes were studied on MCF-7 and MDA-MB-468, during 24 h exposure in MTT assay. Results: The maximum curcumin entrapment (15.5% W/W) and minimum degradation (

In the title compound, C19H23IN2O2, the cyclohexane ring adopts a chair conformation, and the mean plane of the propiolamide unit is approximately perpendicular to the benzene ring [dihedral angle = 88.12 (13)°]. Weak intramolecular C—H...O hydrogen bonding is observed between the carbonyl group and the benzene ring. In the crystal, classical N—H...O hydrogen bonds and weak C—H...O interactions are present.