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Background: The novel bacterial topoisomerase inhibitors (NBTIs) developed in our laboratory show potent on-target enzyme inhibition but suffer from low activity against Gram-negative bacteria. Methods: With the aim of improving the antibacterial activity of our compounds against Gram-negative bacteria, we tested them in combination with different efflux pump inhibitors (EPIs), a strategy that showed promise in several other classes of antimicrobials. We also investigated the combined effect of NBTIs with ATP-competitive inhibitors of bacterial type II topoisomerases (ACIs), as well as the antibiofilm properties of our compounds and the combination with EPIs against early and mature Acietobacter baumannii biofilm. Results: Our results demonstrate that combinations of NBTIs with EPI Phenylalanine-arginyl-β-naphthylamide significantly reduce the corresponding NBTIs' minimal inhibitory concentration values and show potentiation of A. baumannii biofilm inhibition as compared to NBTIs alone. Although combinations of NBITs and ACIs did not show synergistic effects, the FIC index value calculations revealed additive effects for all the combinations of a selected NBTI in combination with three ACIs in all the assayed Gram-negative bacteria from the ESKAPE group. Conclusions: These results show for the first time that combinations of NBTIs with either EPIs or a different class of the topoisomerase inhibitors may be a beneficial strategy to combat difficult-to-treat bacterial infections. [ABSTRACT FROM AUTHOR]

A new group of thiazolidine-2,4-dione derivatives of ciprofloxacin having butyryl linker 3a-l was synthesized via an alkylation of thiazolidine-2,4-diones with butyryl ciprofloxacin with yield range 48–77% andfully characterized by various spectroscopic and analytical tools. Anti-cancer screening outcomes indicated that 3a and 3i possess antiproliferative activities against human melanoma LOX IMVI cancer cell line with IC50 values of 26.7 ± 1.50 and 25.4 ± 1.43 µM, respectively, using doxorubicin and cisplatin as positive controls with an IC50 of 7.03 ± 0.40 and 5.07 ± 0.29 µM, respectively. Additionally, compound 3j showed promising anticancer activity against human renal cancer A498 cell line with IC50 value of 33.9 ± 1.91 µM while doxorubicin and cisplatin showed IC50 values of 3.59 ± 0.20 and 7.92 ± 0.45, respectively. On the other hand, compound 3i did not show considerable anti-bacterial activity against S. aureus, E. coli and P. aeruginosa, and only moderate activity against K. pneumoniae with only a tenth of the activity of ciprofloxacin, confirming the cytotoxicity observed. Mechanistically, compound 3i inhibited both topoisomerase I and II with IC50 of 4.77 ± 0.26 and 15 ± 0.81 µM. Furthermore, it induced cell cycle arrest at S phase in melanoma LOX IMVI cells. Moreover, 3i provoked substantial levels of early, late apoptosis and necrosis in melanoma LOX IMVI cell line comparable to that induced by doxorubicin. Furthermore, compound 3i increased the expression level of active caspase-3 by 49 folds higher in LOX IMVI cell, increased protein expression level of Bax more than the control by 3 folds and inhibited PARP-1by 33% in LOX IMVI. All results were supported by theoretical docking studies on both tested enzymes confirming potential cytotoxicity for the synthesized hybrids. [ABSTRACT FROM AUTHOR]

Abstract A new group of thiazolidine-2,4-dione derivatives of ciprofloxacin having butyryl linker 3a-l was synthesized via an alkylation of thiazolidine-2,4-diones with butyryl ciprofloxacin with yield range 48–77% andfully characterized by various spectroscopic and analytical tools. Anti-cancer screening outcomes indicated that 3a and 3i possess antiproliferative activities against human melanoma LOX IMVI cancer cell line with IC50 values of 26.7 ± 1.50 and 25.4 ± 1.43 µM, respectively, using doxorubicin and cisplatin as positive controls with an IC50 of 7.03 ± 0.40 and 5.07 ± 0.29 µM, respectively. Additionally, compound 3j showed promising anticancer activity against human renal cancer A498 cell line with IC50 value of 33.9 ± 1.91 µM while doxorubicin and cisplatin showed IC50 values of 3.59 ± 0.20 and 7.92 ± 0.45, respectively. On the other hand, compound 3i did not show considerable anti-bacterial activity against S. aureus, E. coli and P. aeruginosa, and only moderate activity against K. pneumoniae with only a tenth of the activity of ciprofloxacin, confirming the cytotoxicity observed. Mechanistically, compound 3i inhibited both topoisomerase I and II with IC50 of 4.77 ± 0.26 and 15 ± 0.81 µM. Furthermore, it induced cell cycle arrest at S phase in melanoma LOX IMVI cells. Moreover, 3i provoked substantial levels of early, late apoptosis and necrosis in melanoma LOX IMVI cell line comparable to that induced by doxorubicin. Furthermore, compound 3i increased the expression level of active caspase-3 by 49 folds higher in LOX IMVI cell, increased protein expression level of Bax more than the control by 3 folds and inhibited PARP-1by 33% in LOX IMVI. All results were supported by theoretical docking studies on both tested enzymes confirming potential cytotoxicity for the synthesized hybrids.

Abstract Suppression of fungal camptothecin (CPT) biosynthesis with the preservation and successive subculturing is the challenge that impedes fungi from the industrial application, so, screening for a novel fungal isolate with a conceivable stable producing potency of CPT was the main objective of this work. Catharanthus roseus with diverse contents of bioactive metabolites could have a plethora of novel endophytes with unique metabolic properties. Among the endophytes of C. roseus, Alternaria brassicicola EFBL-NV OR131587.1 was the highest CPT producer (96.5 μg/L). The structural identity of the putative CPT was verified by HPLC, FTIR, HNMR and LC–MS/MS, with a molecular mass 349 m/z, and molecular fragmentation patterns that typically identical to the authentic one. The purified A. brassicicola CPT has a strong antiproliferative activity towards UO-31 (0.75 μM) and MCF7 (3.2 μM), with selectivity index 30.8, and 7.1, respectively, in addition to resilient activity to inhibit Topo II (IC50 value 0.26 nM) than Topo 1 (IC50 value 3.2 nM). The purified CPT combat the wound healing of UO-31 cells by ~ 52%, stops their matrix formation, cell migration and metastasis. The purified CPT arrest the cellular division of the UO-31 at the S-phase, and inducing their cellular apoptosis by ~ 20.4 folds, compared to the control cells. Upon bioprocessing with the surface response methodology, the CPT yield by A. brassicicola was improved by ~ 3.3 folds, compared to control. The metabolic potency of synthesis of CPT by A. brassicicola was attenuated with the fungal storage and subculturing, losing ~ 50% of their CPT productivity by the 6th month of storage and 6th generation. Practically, the CPT productivity of the attenuated A. brassicicola was restored by addition of 1% surface sterilized leaves of C. roseus, ensuring the eliciting of cryptic gene cluster of A. brassicicola CPT via the plant microbiome-A. brassicicola interactions. So, for the first time, a novel endophytic isolate A. brassicicola, from C. roseus, was explored to have a relatively stable CPT biosynthetic machinery, with an affordable feasibility to restore their CPT productivity using C. roseus microbiome, in addition to the unique affinity of the extracted CPT to inhibit Topoisomerase I and II.

Suppression of fungal camptothecin (CPT) biosynthesis with the preservation and successive subculturing is the challenge that impedes fungi from the industrial application, so, screening for a novel fungal isolate with a conceivable stable producing potency of CPT was the main objective of this work. Catharanthus roseus with diverse contents of bioactive metabolites could have a plethora of novel endophytes with unique metabolic properties. Among the endophytes of C. roseus, Alternaria brassicicola EFBL-NV OR131587.1 was the highest CPT producer (96.5 μg/L). The structural identity of the putative CPT was verified by HPLC, FTIR, HNMR and LC–MS/MS, with a molecular mass 349 m/z, and molecular fragmentation patterns that typically identical to the authentic one. The purified A. brassicicola CPT has a strong antiproliferative activity towards UO-31 (0.75 μM) and MCF7 (3.2 μM), with selectivity index 30.8, and 7.1, respectively, in addition to resilient activity to inhibit Topo II (IC50 value 0.26 nM) than Topo 1 (IC50 value 3.2 nM). The purified CPT combat the wound healing of UO-31 cells by ~ 52%, stops their matrix formation, cell migration and metastasis. The purified CPT arrest the cellular division of the UO-31 at the S-phase, and inducing their cellular apoptosis by ~ 20.4 folds, compared to the control cells. Upon bioprocessing with the surface response methodology, the CPT yield by A. brassicicola was improved by ~ 3.3 folds, compared to control. The metabolic potency of synthesis of CPT by A. brassicicola was attenuated with the fungal storage and subculturing, losing ~ 50% of their CPT productivity by the 6th month of storage and 6th generation. Practically, the CPT productivity of the attenuated A. brassicicola was restored by addition of 1% surface sterilized leaves of C. roseus, ensuring the eliciting of cryptic gene cluster of A. brassicicola CPT via the plant microbiome-A. brassicicola interactions. So, for the first time, a novel endophytic isolate A. brassicicola, from C. roseus, was explored to have a relatively stable CPT biosynthetic machinery, with an affordable feasibility to restore their CPT productivity using C. roseus microbiome, in addition to the unique affinity of the extracted CPT to inhibit Topoisomerase I and II. [ABSTRACT FROM AUTHOR]

New ellipticine analogs with indole cores were synthesized. and evaluated for their anticancer activity. A new compound, scaffolds, revealed broad-spectrum anticancer potential in one-dose and five doses screening. against the full 60-cell line at NCI. Compounds 2a and 3c had been selected for five-dose screening, where they showed marked anticancer activity against the tested cell lines with an average GI50 (MG-MID) value of 2.23 and 0.98 mM, respectively. Compounds 2a, 2b, 2d, 3b, 3c, and 12 showed noted Topoisomerase Type IIβ inhibitory activity with inhibition records 85.45, 94.7, 93.5, 91.6, 89, and 94.5 percent, respectively. Molecular modeling studies and physicochemical parameter calculations of the most active compounds confirmed their safe. drug-like properties. as a promising anticancer class. [ABSTRACT FROM AUTHOR]

Abstract Attenuation of camptothecin (CPT) productivity by fungi with preservation and subculturing is the challenge that halts fungi to be an industrial platform of CPT production. Thus, screening for novel endophytic fungal isolates with metabolic stability for CPT production was the objective. Catharanthus roseus is one of the medicinal plants with diverse bioactive metabolites that could have a plethora of novel endophytes with unique metabolites. Among the endophytes of C. roseus, Aspergillus terreus EFBL-NV OR131583.1 had the most CPT producing potency (90.2 μg/l), the chemical identity of the putative CPT was verified by HPLC, FT-IR, NMR and LC–MS/MS. The putative A. terreus CPT had the same molecular mass (349 m/z), and molecular fragmentation patterns of the authentic one, as revealed from the MS/MS analyses. The purified CPT had a strong activity against MCF7 (5.27 μM) and UO-31 (2.2 μM), with a potential inhibition to Topo II (IC50 value 0.52 nM) than Topo 1 (IC50 value 6.9 nM). The CPT displayed a high wound healing activity to UO-31 cells, stopping their metastasis, matrix formation and cell immigration. The purified CPT had a potential inducing activity to the cellular apoptosis of UO-31 by ~ 17 folds, as well as, arresting their cellular division at the S-phase, compared to the control cells. Upon Plackett–Burman design, the yield of CPT by A. terreus was increased by ~ 2.6 folds, compared to control. The yield of CPT by A. terreus was sequentially suppressed with the fungal storage and subculturing, losing ~ 50% of their CPT productivity by 3rd month and 5th generation. However, the productivity of the attenuated A. terreus culture was completely restored by adding 1% surface sterilized leaves of C. roseus, and the CPT yield was increased over-the-first culture by ~ 3.2 folds (315.2 μg/l). The restoring of CPT productivity of A. terreus in response to indigenous microbiome of C. roseus, ensures the A. terreus-microbiome interactions, releasing a chemical signal that triggers the CPT productivity of A. terreus. This is the first reports exploring the potency of A. terreus, endophyte of C. roseus” to be a platform for industrial production of CPT, with an affordable sustainability with addition of C. roseus microbiome.

Background: The novel bacterial topoisomerase inhibitors (NBTIs) developed in our laboratory show potent on-target enzyme inhibition but suffer from low activity against Gram-negative bacteria. Methods: With the aim of improving the antibacterial activity of our compounds against Gram-negative bacteria, we tested them in combination with different efflux pump inhibitors (EPIs), a strategy that showed promise in several other classes of antimicrobials. We also investigated the combined effect of NBTIs with ATP-competitive inhibitors of bacterial type II topoisomerases (ACIs), as well as the antibiofilm properties of our compounds and the combination with EPIs against early and mature Acietobacter baumannii biofilm. Results: Our results demonstrate that combinations of NBTIs with EPI Phenylalanine-arginyl-β-naphthylamide significantly reduce the corresponding NBTIs’ minimal inhibitory concentration values and show potentiation of A. baumannii biofilm inhibition as compared to NBTIs alone. Although combinations of NBITs and ACIs did not show synergistic effects, the FIC index value calculations revealed additive effects for all the combinations of a selected NBTI in combination with three ACIs in all the assayed Gram-negative bacteria from the ESKAPE group. Conclusions: These results show for the first time that combinations of NBTIs with either EPIs or a different class of the topoisomerase inhibitors may be a beneficial strategy to combat difficult-to-treat bacterial infections.

[Display omitted] Topoisomerase is a ubiquitous enzyme in the control of DNA chain topology. There have been extensive research on topoisomerase inhibitors derived from natural sources, which act as partial inducers of tumor cell apoptosis. However, their specific efficacy in treating hepatocellular carcinoma is relatively unexplored. Hence, this comprehensive review focuses on the structural characteristics and anti-cancer properties of topoisomerase inhibitors in hepatocellular carcinoma. Furthermore, this review is also elucidating the mechanism of action, structure–activity relationships, therapeutic limitations, stage of clinical trials of described classes of natural bioactive compounds as well as their potential application in cancer chemotherapies. This broad understanding of topoisomerase medical biology will provide indispensable framework for enhancing the efficiency of rational anti-hepatocellular carcinoma drug discovery. [ABSTRACT FROM AUTHOR]

Introduction: The increase in survival rates in children treated for cancer has been accompanied by a rise in sequelae in permanent teeth. The aim of the study was to correlate the type of cancer therapy administered to patients during early childhood and the dental sequelae recorded in survivors., Material and Methods: Single-center retrospective cohort study carried out at the Children's University Hospital of Sant Joan de Déu in Barcelona, Spain. Hundred and nine patients who had received cancer treatment during early childhood were randomly examined and grouped according to diagnosis and cancer therapy received. The type of therapy was correlated with the number and severity of dental lesions that patients presented in adolescence., Results: Dental sequelae of some kind were present in 85.3% of patients. Microdontia was the most prevalent (52.3%). Treatment with alkylating agents had a relative risk of presenting moderate lesions of 3.36 (1.18-9.60), and one of 2.29 (1.07-4.91) of presenting severe lesions. Topoisomerase inhibitors and cytotoxic antibiotics presented relative risks of 1.6 (1.07-2.38) and 2.08 (1.02-4.26) of root alterations and agenesis, respectively., Conclusions: Treatment with alkylating agents together with cytotoxic antibiotics and topoisomerase inhibitors was associated with a higher relative risk of microdontia, agenesis, and root shortening., (© 2022 The Authors. Oral Diseases published by Wiley Periodicals LLC.)

Drug-free macromolecular therapeutics (DFMT) utilizes modified monoclonal antibodies (or antibody fragments) to generate antigen-crosslinking-induced apoptosis in target cells. DFMT is a two-component system containing a morpholino oligonucleotide (MORF1) modified antibody (Ab-MORF1) and human serum albumin conjugated with multiple copies of complementary morpholino oligonucleotide (MORF2), (HSA-(MORF2) x ). The two components recognize each other via the Watson-Crick base pairing complementation of their respective MORFs. One HSA-(MORF2) x molecule can hybridize with multiple Ab-MORF1 molecules on the cell surface, thus serving as the therapeutic crosslink-inducing mechanism of action. Herein, various anti-neoplastic agents in combination with the anti-CD20 Obinutuzumab (OBN)-based DFMT system are examined. Three different classes of chemotherapies are examined: DNA alkylating agents; proliferation pathway inhibitors; and DNA replication inhibitors. Chou-Talalay combination index mathematics is utilized to determine which drugs engaged synergistically with OBN-based DFMT. It is determined that OBN-based DFMT synergizes with topoisomerase inhibitors and DNA nucleotide analogs but is antagonistic with proliferation pathway inhibitors. Cell mechanism experiments are performed to analyze points of synergism or antagonism by investigating Ca 2+ influx, mitochondrial health, lysosomal stability, and cell cycle arrest. Finally, the synergistic drug combinatorial effects of OBN-based DFMT with etoposide in vivo are demonstrated using a human xenograft non-Hodgkin's lymphoma mouse model., (© 2023 Wiley-VCH GmbH.)

Xanthone-chromanone homo- or heterodimers are regarded as a novel class of topoisomerase (Topo) inhibitors; however, limited information about these compounds is currently available. Here, 14 new ( 1 - 14 ) and 6 known tetrahydroxanthone chromanone homo- and heterodimers ( 15 - 20 ) are reported as isolated from Penicillium chrysogenum C-7-2-1. Their structures and absolute configurations were unambiguously demonstrated by a combination of spectroscopic data, single-crystal X-ray diffraction, modified Mosher's method, and electronic circular dichroism analyses. Plausible biosynthetic pathways are proposed. For the first time, it was discovered that tetrahydroxanthones can convert to chromanones in water, whereas chromone dimerization does not show this property. Among them, compounds 5 , 7 , 8 , and 16 exhibited significant cytotoxicity against H23 cell line with IC 50 values of 6.9, 6.4, 3.9, and 2.6 μM, respectively.

Camptothecin is a pentacyclic natural alkaloid that inhibits the hTop1 enzyme involved in DNA transcription and cancer cell growth. Camptothecin structure pitfalls prompted us to design new congeners using a structure simplification strategy to reduce the ring extension number from pentacyclic to tetracyclic while maintaining potential stacking of the new compounds with the DNA base pairs at the Top1-mediated cleavage complex and aqueous solubility, as well as minimizing compound-liver toxicity. The principal axis of this study was the verification of hTop1 inhibiting activity as a possible mechanism of action and the elaboration of new simplified inhibitors with improved pharmacodynamic and pharmacokinetic profiling using three structure panels (A-C) of (isoquinolinoimidazoquinazoline), (imidazoquinazoline), and (imidazoisoquinoline), respectively. DNA relaxation assay identified five compounds as hTop1 inhibitors belonging to the imidazoisoquinolines 3a,b, the imidazoquinazolines 12, and the isoquinolinoimidazoquinazolines 7a,b. In an MTT cytotoxicity assay against different cancer cell lines, compound 12 was the most potent against HOS bone cancer cells (IC 50  = 1.47 μM). At the same time, the other inhibitors had no detectable activity against any cancer cell type. Compound (12) demonstrated great penetrating power in the HOS cancer cells' 3D-multicellular tumor spheroid model. Bioinformatics research of the hTop1 gene revealed that the TP53 cell proliferative gene is in the network of hTop1. The finding is confirmed empirically using the gene expression assay that proved the increase in p53 expression. The impact of structure simplification on compound 12 profile, characterized by the absence of acute oral liver toxicity when compared to Doxorubicin as a standard inhibitor, the lethal dose measured on Swiss Albino female mice and reported at LD 50  = 250 mg/kg, and therapeutic significance in reducing colon adenocarcinoma tumor volume by 75.36 % after five weeks of treatment with compound 12. The molecular docking solutions of the active CPT-based derivative 12 and the inactive congener 14 into the active site of hTop1 and the activity cliffing of such MMP directed us to recommend the addition of HBD and HBA variables to compound 12 imidazoquinazoline core scaffold to enhance the potency via hydrogen bond formation with the major groove amino acids (Asp533, Lys532) as well as maintaining the hydrogen bond with the minor groove amino acid Arg364., 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 © 2023 Elsevier Masson SAS. All rights reserved.)