Production and bioprocessing of Taxol from Aspergillus niger, an endophyte of Encephalartos whitelockii, with a plausible biosynthetic stability: antiproliferative activity and cell cycle analysis.

The biosynthetic potency of Taxol by fungi raises their prospective to be a platform for commercial production of Taxol, nevertheless, the attenuation of its productivity with the fungal storage, is the challenge. Thus, screening for a novel fungal isolate inhabiting ethnopharmacological plants, with a plausible metabolic stability for Taxol production could be one of the most affordable approaches. Aspergillus niger OR414905.1, an endophyte of Encephalartos whitelockii, had the highest Taxol productivity (173.9 µg/L). The chemical identity of the purified Taxol was confirmed by HPLC, FTIR, and LC-MS/MS analyses, exhibiting the same molecular mass (854.5 m/z) and molecular fragmentation pattern of the authentic Taxol. The purified Taxol exhibited a potent antiproliferative activity against HepG-2, MCF-7 and Caco-2, with IC50 values 0.011, 0.016, and 0.067 µM, respectively, in addition to a significant activity against A. flavus, as a model of human fungal pathogen. The purified Taxol displayed a significant effect against the cellular migration of HepG-2 and MCF-7 cells, by ~ 52-59% after 72 h, compared to the control, confirming its interference with the cellular matrix formation. Furthermore, the purified Taxol exhibited a significant ability to prompt apoptosis in MCF-7 cells, by about 11-fold compared to control cells, suppressing their division at G2/M phase. Taxol productivity by A. niger has been optimized by the response surface methodology with Plackett-Burman Design and Central Composite Design, resulting in a remarkable ~ 1.6-fold increase (279.8 µg/L), over the control. The biological half-life time of Taxol productivity by A. niger was ~ 6 months of preservation at 4 â„ƒ, however, the Taxol yield by A. niger was partially restored in response to ethyl acetate extracts of E. whitelockii, ensuring the presence of plant-derived signals that triggers the cryptic Taxol encoding genes.

Design, concise synthesis and evaluation of novel amide-based combretastatin A-4 analogues as potent tubulin inhibitors.

As our ongoing work, a novel series of the amide-based CA-4 analogues were successfully designed, synthesized, and explored for their biological evaluation. Among these compounds, 7d and 8a illustrated most potent antiproliferative activity toward A549, HeLa, HCT116, and HT-29 cell lines. Most importantly, these two compounds didn't display noticeable cytotoxic activity on the non-tumoural cell line HEK-293. Further mechanism studies revealed that analogue 8a was identified as a novel tubulin polymerization inhibitor with an IC50 value of 6.90 µM, which is comparable with CA-4. The subsequent investigations unveiled that analogue 8a not only effectively caused cell cycle arrest at the G2/M phase but also induced apoptosis in A549 cells via a concentration-dependent manner. The molecular docking revealed that 8a could occupy well the colchicine-binding site of tubulin. Collectively, these findings indicate that amide-based CA-4 scaffold could be worthy of further evaluation for development of novel tubulin inhibitors with improved safety profile.

Antiproliferative activities through accelerating autophagic flux by basidalin and its analogs in human cancer cells.

Basidalin, isolated from the basidiomycete Leucoagaricus naucina, has previously demonstrated antibacterial and antitumor properties against murine cancer cells in vivo, but its effects on human cancer cells remain unknown. In this study, we found that basidalin possesses antiproliferative activity against human cancer cell lines. To elucidate the antiproliferative mechanism of basidalin, we focused on autophagy. Treatment with basidalin led to an increase in LC3-II expression level, and accelerated autophagic flux through an mTOR-independent pathway. Moreover, according to the structure-activity relationship analysis-including newly synthesized basidalin analogs-the formyl group, not the amino group, contributes to the antiproliferative activities of basidalin against human cancer cells. Additionally, the antiproliferative activity of basidalin analogs was strongly correlated with autophagy-inducing activity, indicating that basidalin exhibits antiproliferative activity through autophagy induction. These data suggest that basidalin, characterized by its ability to upregulate autophagic flux, emerges as a novel anticancer drug.

Discovery of harmiprims, harmine-primaquine hybrids, as potent and selective anticancer and antimalarial compounds.

Although cancer and malaria are not etiologically nor pathophysiologically connected, due to their similarities successful repurposing of antimalarial drugs for cancer and vice-versa is known and used in clinical settings and drug research and discovery. With the growing resistance of cancer cells and Plasmodium to the known drugs, there is an urgent need to discover new chemotypes and enrich anticancer and antimalarial drug portfolios. In this paper, we present the design and synthesis of harmiprims, hybrids composed of harmine, an alkaloid of the ß-carboline type bearing anticancer and antiplasmodial activities, and primaquine, 8-aminoquinoline antimalarial drug with low antiproliferative activity, covalently bound via triazole or urea. Evaluation of their antiproliferative activities in vitro revealed that N-9 substituted triazole-type harmiprime was the most selective compound against MCF-7, whereas C1-substituted ureido-type hybrid was the most active compound against all cell lines tested. On the other hand, dimeric harmiprime was not toxic at all. Although spectrophotometric studies and thermal denaturation experiments indicated binding of harmiprims to the ds-DNA groove, cell localization showed that harmiprims do not enter cell nucleus nor mitochondria, thus no inhibition of DNA-related processes can be expected. Cell cycle analysis revealed that C1-substituted ureido-type hybrid induced a G1 arrest and reduced the number of cells in the S phase after 24 h, persisting at 48 h, albeit with a less significant increase in G1, possibly due to adaptive cellular responses. In contrast, N-9 substituted triazole-type harmiprime exhibited less pronounced effects on the cell cycle, particularly after 48 h, which is consistent with its moderate activity against the MCF-7 cell line. On the other hand, screening of their antiplasmodial activities against the erythrocytic, hepatic, and gametocytic stages of the Plasmodium life cycle showed that dimeric harmiprime exerts powerful triple-stage antiplasmodial activity, while computational analysis showed its binding within the ATP binding site of PfHsp90.

Identification of thienopyrimidine derivatives tethered with sulfonamide and other moieties as carbonic anhydrase inhibitors: Design, synthesis and anti-proliferative activity.

Eighteen novel compounds harboring the privileged thienopyrimidine scaffold (5a-q, and 6a),were designed based on molecular hybridization strategy. These compounds were synthesized and tested for their inhibitory activity against four different carbonic anhydrase isoforms: CA I, II, IX, and XII. Microwave and conventional techniques were applied for their synthesis. Compounds 5b, 5g, 5l, and 5p showed the highest inhibition activity against the four CA isoforms. Compound 5p exhibited promising inhibitory activity against CA II, CA IX and CA XII with KI values of8.6, 13.8, and 19 nM, respectively, relative to AAZ, where KIs = 12, 25, and 5.7 nM, respectively. Also, compound 5 l showed significant activity against the tumor-associated isoform CA IX with KI = 16.1 nM. All the newly synthesized compounds were also screened for their anticancer activity against NCI 60 cancer cell lines at a 10 µM concentration. Compound 5n showed 80.38, 83.95, and 87.39 % growth inhibition against the leukemic cell lines CCRF-CEM, HL-60 (TB), and RPMI-8226, respectively. Also, 5 h showed 87.57 % growth inhibition against breast cancer cell line MDA-MB-468; and 66.58 and 60.95 % inhibitionagainst renal cancer cell lines UO-31, and ACHN, respectively. A molecular docking studywas carried out to predict binding modes of our synthesized compounds in the binding pockets of the four carbonic anhydrase isoforms, and results revealed that compounds 5b, 5g, 5l, and 5p succeeded in mimicking the binding mode of AAZ through metal coordination with Zn+2 ion and binding to the amino acids Thr199, His94, and His96 that are critical for activity.

Design and bio-evaluation of novel millepachine derivatives targeting tubulin colchicine binding site for treatment of osteosarcoma.

Microtubules are recognized as an appealing target for cancer treatment. We designed and synthesized of novel tubulin colchicine binding site inhibitors based on millepachine. Biological evaluation revealed compound 5h exhibited significant antiproliferative activity against osteosarcoma cell U2OS and MG-63. And compound 5h also remarkably inhibited tubulin polymerization. Further investigations indicated compound 5h not only arrest U2OS cells cycle at the G2/M phases, but also induced U2OS cells apoptosis in dose-dependent manners. Moreover, compound 5h was verified to inhibit cell migration and angiogenesis of HUVECs, induce mitochondrial membrane potential decreased and promoted the elevation of ROS levels. Furthermore, compound 5h exhibited remarkable effects on tumor growth in vivo, and the TGI rate was up to 84.94 % at a dose of 20 mg/kg without obvious toxicity. These results indicated that 5h may be an appealing tubulin inhibitor for treatment of osteosarcoma.

Biological activity and computational analysis of novel acrylonitrile derived benzazoles as potent antiproliferative agents for pancreatic adenocarcinoma with antioxidative properties.

Continuing our research into the anticancer properties of acrylonitriles, we present a study involving the design, synthesis, computational analysis, and biological assessment of novel acrylonitriles derived from methoxy, hydroxy, and N-substituted benzazole. Our aim was to examine how varying the number of methoxy and hydroxy groups, as well as the N-substituents on the benzimidazole core, influences their biological activity. The newly synthesized acrylonitriles exhibited strong and selective antiproliferative effects against the Capan-1 pancreatic adenocarcinoma cell line, with IC50 values ranging from 1.2 to 5.3 µM. Consequently, these compounds were further evaluated in three other pancreatic adenocarcinoma cell lines, while their impact on normal PBMC cells was also investigated to determine selectivity. Among these compounds, the monohydroxy-substituted benzimidazole derivative 27 emerged with the most profound and broad-spectrum anticancer antiproliferative activity being emerged as a promising lead candidate. Moreover, a majority of the acrylonitriles in this series exhibited significant antioxidative activity, surpassing that of the reference molecule BHT, as demonstrated by the FRAP assay (ranging from 3200 to 5235 mmolFe2+/mmolC). Computational analysis highlighted the prevalence of electron ionization in conferring antioxidant properties, with computed ionization energies correlating well with observed activities.

Advances in synthesis and biological evaluation of CDK2 inhibitors for cancer therapy.

One of the leading causes of mortality in the world is cancer. This disease occurs when responsible genes that regulate the cell cycle become inactive due to internal or external factors. Specifically, the G1/S and S/G2 transitions in the cell cycle are controlled by a protein called cyclin-dependent kinase 2 (CDK2). CDKs, which play a crucial role in managing the cell cycle, have been a wide area of research in cancer treatment. Over the past 11 years, significant research has been made in identifying potent, targeted, and efficient inhibitors of CDK2. In this summary, we have summarized recent developments in the synthesis and biological evaluation of CDK2 inhibitors.

Design, synthesis, and biological evaluation of N-(pyridin-3-yl)pyrimidin-4-amine analogues as novel cyclin-dependent kinase 2 inhibitors for cancer therapy.

The discovery and development of CDK2 inhibitors has currently been validated as a hot topic in cancer therapy. Herein, a series of novel N-(pyridin-3-yl)pyrimidin-4-amine derivatives were designed and synthesized as potent CDK2 inhibitors. Among them, the most promising compound 7l presented a broad antiproliferative efficacy toward diverse cancer cells MV4-11, HT-29, MCF-7, and HeLa with IC50 values of 0.83, 2.12, 3.12, and 8.61 µM, respectively, which were comparable to that of Palbociclib and AZD5438. Interestingly, these compounds were less toxic on normal embryonic kidney cells HEK293 with high selectivity index. Further mechanistic studies indicated 7l caused cell cycle arrest and apoptosis on HeLa cells in a concentration-dependent manner. Moreover, 7l manifested potent and similar CDK2/cyclin A2 nhibitory activity to AZD5438 with an IC50 of 64.42 nM. These findings revealed that 7l could serve as ahighly promisingscaffoldfor CDK2 inhibitors as potential anticancer agents and functional probes.

Novel guanidine derivatives targeting leukemia as selective Src/Abl dual inhibitors: Design, synthesis and anti-proliferative activity.

A new series of benzene-sulfonamide derivatives 3a-i was designed and synthesized via the reaction of N-(pyrimidin-2-yl)cyanamides 1a-i with sulfamethazine sodium salt 2 as dual Src/Abl inhibitors. Spectral data IR, 1H-, 13C- NMR and elemental analyses were used to confirm the structures of all the newly synthesized compounds 3a-i and 4a-i. Crucially, we screened all the synthesized compounds 3a-i against NCI 60 cancer cell lines. Among all, compound 3b was the most potent, with IC50 of 0.018 µM for normoxia, and 0.001 µM for hypoxia, compared to staurosporine against HL-60 leukemia cell line. To verify the selectivity of this derivative, it was assessed against a panel of tyrosine kinase EGFR, VEGFR-2, B-raf, ERK, CK1, p38-MAPK, Src and Abl enzymes. Results revealed that compound 3b can effectively and selectively inhibit Src/Abl with IC500.25 µM and Abl inhibitory activity with IC500.08 µM, respectively, and was found to be more potent on these enzymes than other kinases that showed the following results: EGFR IC500.31 µM, VEGFR-2 IC500.68 µM, B-raf IC500.33 µM, ERK IC501.41 µM, CK1 IC500.29 µM and p38-MAPK IC500.38 µM. Moreover, cell cycle analysis and apoptosis performed to compound 3b against HL-60 suggesting its antiproliferative activity through Src/Abl inhibition. Finally, molecular docking studies and physicochemical properties prediction for compounds 3b, 3c, and 3 h were carried out to investigate their biological activities and clarify their bioavailability.

Effect of phenolic-hydroxy-group incorporation on the biological activity of a simplified aplysiatoxin analog with an (R)-(-)-carvone-based core.

We synthesized a phenolic hydroxy group-bearing version (1) of a simplified analog of aplysiatoxin comprising a carvone-based conformation-controlling unit. Thereafter, we evaluated its antiproliferative activity against human cancer cell lines and its binding affinity to protein kinase C (PKC) isozymes. The antiproliferative activity and PKC-binding ability increased with the introduction of the phenolic hydroxy group. The results of molecular dynamics simulations and subsequent relative binding free-energy calculations conducted using an alchemical transformation procedure showed that the phenolic hydroxy group in 1 could form a hydrogen bond with a phospholipid and the PKC. The former hydrogen bonding formation facilitated the partitioning of the compound from water to the phospholipid membrane and the latter compensated for the loss of hydrogen bond with the phospholipid upon binding to the PKC. This information may facilitate the development of rational design methods for PKC ligands with additional hydrogen bonding groups.

3-aryl-4-(3,4,5-trimethoxyphenyl)pyridines inhibit tubulin polymerisation and act as anticancer agents.

A series of cis-restricted 3-aryl-4-(3,4,5-trimethoxyphenyl)pyridines as novel tubulin polymerisation inhibitors was designed based on molecular docking. Compound 9p, exhibited potent antiproliferative activity against HeLa, MCF-7, and A549 cell lines. Mechanism studies indicated that 9p potently inhibited tubulin polymerisation and disrupted the microtubule dynamics of tubulin in HeLa cells. Moreover, 9p could cause G2/M phase cell cycle arrest and apoptosis in HeLa cells. In addition, the prediction of physicochemical properties disclosed that 9p conformed well to the Lipinski's rule of five. The initial results suggest that the 3-aryl-4-(3,4,5-trimethoxyphenyl)pyridines could serve as a promising scaffold for the development of novel anticancer drugs.

Comparative Evaluation of the Antibacterial and Antitumor Activities of 9-Phenylfascaplysin and Its Analogs.

Based on the results of our own preliminary studies, the derivative of the marine alkaloid fascaplysin containing a phenyl substituent at C-9 was selected to evaluate the therapeutic potential in vivo and in vitro. It was shown that this compound has outstandingly high antimicrobial activity against Gram-positive bacteria, including antibiotic-resistant strains in vitro. The presence of a substituent at C-9 of the framework is of fundamental importance, since its replacement to neighboring positions leads to a sharp decrease in the selectivity of the antibacterial action, which indicates the presence of a specific therapeutic target in bacterial cells. On a model of the acute bacterial sepsis in mice, it was shown that the lead compound was more effective than the reference antibiotic vancomycin seven out of nine times. However, ED50 value for 9-phenylfascaplysin (7) was similar for the unsubstituted fascaplysin (1) in vivo, despite the former being significantly more active than the latter in vitro. Similarly, assessments of the anticancer activity of compound 7 against various variants of Ehrlich carcinoma in mice demonstrated its substantial efficacy. To conduct a structure-activity relationship (SAR) analysis and searches of new candidate compounds, we synthesized a series of analogs of 9-phenylfascaplysin with varying aryl substituents. However, these modifications led to the reduced aqueous solubility of fascaplysin derivatives or caused a loss of their antibacterial activity. As a result, further research is required to explore new avenues for enhancing its pharmacokinetic characteristics, the modification of the heterocyclic framework, and optimizing of treatment regimens to harness the remarkable antimicrobial potential of fascaplysin for practical usage.

Total Synthesis and Biological Profiling of Putative (±)-Marinoaziridine B and (±)-N-Methyl Marinoaziridine A.

The total synthesis of two new marine natural products, (±)-marinoaziridine B 7 and (±)-N-methyl marinoaziridine A 8, was accomplished. The (±)-marinoaziridine 7 was prepared in a six-step linear sequence with a 2% overall yield. The key steps in our strategy were the preparation of the chiral epoxide (±)-5 using the Johnson Corey Chaykovsky reaction, followed by the ring-opening reaction and the Staudinger reaction. The N,N-dimethylation of compound (±)-7 gives (±)-N-methyl marinoaziridine A 8. The NMR spectra of synthetized (±)-marinoaziridine B 7 and isolated natural product did not match. The compounds are biologically characterized using relevant in silico, in vitro and in vivo methods. In silico ADMET and bioactivity profiling predicted toxic and neuromodulatory effects. In vitro screening by MTT assay on three cell lines (MCF-7, H-460, HEK293T) showed that both compounds exhibited moderate to strong antiproliferative and cytotoxic effects. Antimicrobial tests on bacterial cultures of Escherichia coli and Staphylococcus aureus demonstrated the dose-dependent inhibition of the growth of both bacteria. In vivo toxicological tests were performed on zebrafish Danio rerio and showed a significant reduction of zebrafish mortality due to N-methylation in (±)-8.

Antioxidant Activity, Inhibition of Intestinal Cancer Cell Growth and Polyphenolic Compounds of the Seagrass Posidonia oceanica's Extracts from Living Plants and Beach Casts.

The aim of the present study was to investigate the use of Posidonia oceanica for making products beneficial for human health. Firstly, we demonstrated that the antioxidant defense (i.e., SOD and APX activity) of P. oceanica's living leaves (LP) has low efficacy, as they partly neutralize the produced H2O2. However, high H2O2 levels led LP to produce, as a response to oxidative stress, high phenolic content, including chicoric acid, p-coumaric acid, caftaric acid, trans-cinnamic and rutin hydrate, as shown by UHPLC-DAD analysis. In addition, LP extracts inhibited intestinal cancer cell proliferation. Moreover, P. oceanica's beach casts consisting of either Wet 'Necromass' (WNP) or Dry 'Necromass' (DNP) were used for preparing extracts. Both DNP and WNP exhibited antioxidant and antiproliferative activities, although lower as compared to those of LP extracts. Although both P. oceanica's meadows and beach casts are considered priority habitats in the Mediterranean Sea due to their high ecological value, legislation framework for beach casts forbidding their removal is still missing. Our results suggested that both LP and DNP could be utilized for the production of high-added value products promoting human health, provided that a sustainability management strategy would be applied for P. oceanica's meadows and beach casts.

Antiproliferative Activities of Cynaropicrin and Related Compounds against Cancer Stem Cells.

Glioblastoma (GBM) has a high mortality rate despite the availability of various cancer treatment options. Although cancer stem cells (CSCs) have been associated with poor prognosis and metastasis, and play an important role in the resistance to existing anticancer drugs and radiation; no CSC-targeting drugs are currently approved in clinical practice. Therefore, the development of antiproliferative agents against CSCs is urgently required. In this study, we evaluated the antiproliferative activities of 21 sesquiterpenoids against human GBM U-251 MG CSCs and U-251 MG non-CSCs. Particularly, the guaianolide sesquiterpene lactone cynaropicrin (1) showed strong antiproliferative activity against U-251 MG CSCs (IC50 = 20.4 µM) and U-251 MG non-CSCs (IC50 = 10.9 µM). Accordingly, we synthesized six derivatives of 1 and investigated their structure-activity relationships. Most of the guaianolide sesquiterpene lactones with the α-methylene-γ-butyrolactone moiety showed antiproliferative activities against U-251 MG cells. We conclude that the 5,7,5-ring and the α-methylene-γ-butyrolactone moiety are both important for antiproliferative activities against U-251 MG cells. The results of this study suggest that the α,ß-unsaturated carbonyl moiety, which has recently become a research hotspot in drug discovery, is the active center of 1. Therefore, we consider 1 as a potential lead for developing novel drugs targeting CSCs.

Anticancer Potential of the S-Heterocyclic Ring Containing Drugs and its Bioactivation to Reactive Metabolites.

Sulfur-containing heterocyclic derivatives have been disclosed for binding with a wide range of cancer-specific protein targets. Various interesting derivatives of sulfur-containing heterocyclics such as benzothiazole, thiazole, thiophene, thiazolidinedione, benzothiophene, and phenothiazine, etc have been shown to inhibit diverse signaling pathways implicated in cancer. Significant progress has also been made in molecular targeted therapy against specific enzymes such as kinase receptors due to potential binding interactions inside the ATP pocket. Sulfur-containing heterocyclic ring metal complexes i. e., benzothiazole, thiazole, thiophene, benzothiophene and phenothiazines are among the most promising active anticancer compounds. However, sulfur heteroaromatic rings, particularly thiophene, are of high structural alert due to their metabolism to reactive metabolites. The mere presence of a structural alert itself does not determine compound toxicity therefore, this review focuses on some specific findings that shed light on factors influencing the toxicity. In the current review, synthetic strategies of introducing the sulfur core ring in the synthesized derivatives are discussed with their structure-activity relationships to enhance our understanding of toxicity mechanisms and develop safer therapeutic options. The sulfur-containing marketed anticancer drugs included in this review direct the synthesis of novel compounds and will help in the development of potent, safer sulfur-based anticancer drugs in near future.

Chemical Characterization, DNA-Damage Protection, Antiproliferative Activity and in Silico Studies of the Essential Oils from Perralderia coronopifolia Coss.

In this study, for the first time, we analyzed the chemical composition of essential oils (EOs) steam-distilled from the flowers and leaves of Perralderia coronopifolia by GC-FID/MS. The objective was to explore new anticancer and antioxidant bioactive substances and understand their mechanisms of action through the use of plant-derived natural products. The major chemical components characterizing the EOs were cis-chrysanthenyl acetate 1, 6-oxocyclonerolidol 2, cis-8-acetoxychrysanthenyl acetate 3, and 6α-hydroxycyclonerolidol 4, respectively. Furthermore, the EOs inhibited cell proliferation in HeLa (human cervix carcinoma) and PC3 (human prostate cancer) cells and protected plasmid DNA from oxidative damage caused by UV-photolyzed H2 O2 . Employing a molecular docking study, we elucidated the main compounds' inhibition mechanisms. Consequently, the antitumor activity could be related to the inhibitory property of compound 3 against CDC25B phosphatase. The evaluation of ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties and the density functional theory (DFT) calculations of the major compounds, especially compound 3, offer potential insights for designing and developing new cancer drug candidates. In conclusion, our study provides a framework for future research and development in the field by establishing a scientific foundation for the use of Perralderia coronopifolia essential oils as a prospective source of antioxidant and anticancer agents.

Quinazoline-chalcone hybrids as HDAC/EGFR dual inhibitors: Design, synthesis, mechanistic, and in-silico studies of potential anticancer activity against multiple myeloma.

Two new series of quinazoline-chalcone hybrids were designed, synthesized as histone deacetylase (HDAC)/epidermal growth factor receptor (EGFR) dual inhibitors, and screened in vitro against the NCI 60 human cancer cell line panel. The most potent derivative, compound 5e bearing a 3,4,5-trimethoxyphenyl chalcone moiety, showed the most effective growth inhibition value against the panel of NCI 60 human cancer cell lines. Thus, it was selected for further investigation for NCI 5 log doses. Interestingly, this trimethoxy-substituted analog inhibited the proliferation of Roswell Park Memorial Institute (RPMI)-8226 cells by 96%, at 10 µM with IC50 = 9.09 ± 0.34 µM and selectivity index = 7.19 against normal blood cells. To confirm the selectivity of this compound, it was evaluated against a panel of tyrosine kinase enzymes. Mechanistically, it successfully and selectively inhibited HDAC6, HDAC8, and EGFR with IC50 = 0.41 ± 0.015, 0.61 ± 0.027, and 0.09 ± 0.004 µM, respectively. Furthermore, the selected derivative induced apoptosis via the mitochondrial apoptotic pathway by raising the Bax/Bcl-2 ratio and activating caspases 3, 7, and 9. Also, the flow cytometry analysis of RPMI-8226 cells showed that the trimethoxy-substituted analog produced cell cycle arrest in the G1 and S phases at 55.82%. Finally, an in silico study was performed to explore the binding interaction of the most active compound within the zinc-containing binding site of HDAC6 and HDAC8.

Synthesis of 2-phenylnaphthalenoid amide derivatives and their topoisomerase IIα inhibitory and antiproliferative activities.

Topoisomerases are highly associated with cell proliferation, becoming an important target for the development of antitumor drugs. 2-Phenylnaphthalenoids (2PNs) have been identified as human DNA topoisomerase IIα (TopoIIα) inhibitors. In this study, based on the 2PN scaffold, 20 amide derivatives (J1-J10, K1-K10) were synthesized. Among them, K10 showed high TopoIIα inhibitory activity and stronger antiproliferation activity against HepG-2 and MDA-MB-231 cells (IC50 0.33 and 0.63 µM, respectively) than the positive control VP-16 (IC50 9.19 and 10.86 µM) and the lead F2 (IC50 0.64 and 1.51 µM). Meanwhile, K10 could also inhibit migration and promote apoptosis of HepG-2 and MDA-MB-231 cells. Therefore, K10 can be developed into a potent TopoIIα inhibitor as an antitumor agent. The structure-activity relationship was also discussed.