Design, Synthesis, Anticancer Evaluation, and Molecular Docking Studies of Oxazole-Incorporated Naphthyridine Derivatives.

A novel series of oxazole incorporated naphthyridine (21 a-j) derivatives were designed and, synthesized followed by screening of their anticancer activity profiles against human breast cancer (MCF-7), human lung cancer (A549) and human prostate (PC3 & DU-145) cancer cell lines by employing MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide] assay using etoposide as the positive control. Of these compounds, N-(6-chloro-3-(4-(3,4,5-trimethoxyphenyl)oxazol-2-yl)-1,5-naphthyridin-4-yl)oxazol-2-amine with 3,4,5-trimethoxy substituent on the aryl moiety attached to oxazole ring showed potent anticancer activity against PC3, A549, MCF-7, and DU-145 cell lines with IC50 values of 0.13±0.095 µM; 0.10±0.084 µM; 0.18±0.087 µM and 0.15±0.076 µM respectively. Apart from this, compounds N-(6-chloro-3-(4-(3,5-dimethoxyphenyl)oxazol-2-yl)-1,5-naphthyridin-4-yl)oxazol-2-amine, N-(6-chloro-3-(4-(4-methoxyphenyl)oxazol-2-yl)-1,5-naphthyridin-4-yl)oxazol-2-amine, and N-(6-chloro-3-(4-(3,5-dimethylphenyl)oxazol-2-yl)-1,5-naphthyridin-4-yl)oxazol-2-amine also showed better anticancer activities against four cancer cell lines screened for. These activities were also validated through the molecular docking simulations, which further indicated demonstration of better interaction energy and profile by these compounds.

Design, Synthesis, and Biological Evaluation of 1,2,4-Thiadiazole-1,2,4-Triazole Derivatives Bearing Amide Functionality as Anticancer Agents.

A novel library of amide functionality having 1,2,4-thiadiazole-1,2,4-triazole (8a-j) analogs was designed, synthesized, and structures were characterized by 1H NMR, 13C NMR, and mass (ESI-MS) spectral data. Further, all compounds were evaluated for their anticancer activities against four different cancer cell lines including breast cancer (MCF-7, MDA MB-231), lung cancer (A549), and prostate cancer (DU-145) by MTT reduction assay method, and etoposide acts as a standard drug. The results confirmed that majority of the synthesized compounds showed moderate to potent anticancer activities aligned with four cell lines. Among the synthesized compounds, 8b, 8c, 8d, 8e, 8g and 8i displayed more potent activity along with inhibitory concentration values ranging from 0.10 ± 0.084 to 11.5 ± 6.49 µM than the standard IC50 values, which ranges from 1.91 ± 0.84 to 3.08 ± 0.135 µM, respectively.

Stereoselective total synthesis of Patulolide C.

Stereoselective total synthesis of Patulolide C has been accomplished from easily available and inexpensive (S)-chiral epoxide. The key steps involved in the concise synthesis of Patulolide C utilizes ring opening of chiral epoxide, cleavage of 1,2-diol, deprotection of benzyl ether of hydroxyl acid and Yamaguchi macrolactonisation dilution conditions as key steps. The advantage of this method include inexpensive starting material, mild reaction conditions and high purity of products.

Synthesis, antiproliferative and apoptosis induction potential activities of novel bis(indolyl)hydrazide-hydrazone derivatives.

In recent years, indole-indazolyl hydrazide-hydrazone derivatives with strong cell growth inhibition and apoptosis induction characteristics are being strongly screened for their cancer chemo-preventive potential. In the present study, N-methyl and N,N-dimethyl bis(indolyl)hydrazide-hydrazone analog derivatives were designed, synthesized and allowed to evaluate for their anti-proliferative and apoptosis induction potential against cervical (HeLa), breast (MCF-7 and MDA-MB-231) and lung (A549) cancer cell lines relative to normal HEK293 cells. The MTT assay in conjunction with mitochondrial potential assays and the trypan blue dye exclusion were employed to ascertain the effects of the derivatives on the cancer cells. Further, mechanistic studies were conducted on compound 14a to understand the biochemical mechanisms and functional interactions with various signaling pathways triggered in HeLa and MCF-7 cells. Compound 14a induced apoptosis via caspase independent pathway through the participation of mitogen-activated protein kinases (MAPK) such as extracellular signal related kinase (ERK) and p38 as well as p53 pathways. It originates the activation of pro-apoptotic proteins such as Bak and Mcl-1s and also strongly induced the generation of reactive oxygen species. In downstream signaling pathway, activated p53 protein interacted with MAPK pathways, including SAPK/c-Jun N-terminal protein kinase (JNK), p38 and ERK kinases resulting in apoptotic cell death. The involvement of MAPK cascades such as p38, ERK and p38 on compound 14a induced apoptotic cell death was evidenced by the fact that the inclusion of specific inhibitors of p38, ERK1/2 and JNK MAPK (SB2035809, PD98059 and SP600125) prevented the compound 14a towards induced apoptosis. The results clearly showed that MAP kinase cascades were crucial for apoptotic response in compound 14a induced cellular killing and were dependent on p53 activity. Based on the results, compound 14a was identified as a promising candidate for cancer therapeutics and these findings furnish a basis for further in vivo experiments on anti-proliferative activity.

An alternative stereoselective total synthesis of (-)-pyrenophorol.

The total synthesis of 16-membered C2-Symmetric dilactone (-)-Pyrenophorol was accomplished starting from commercially available (S)-epoxide prepared by hydrolytic kinetic resolution of (±) - epoxide with key steps of Grignard reaction, Swern oxidation, Wittig reaction and cyclization was achieved by intermolecular Mitsunobu cyclization. The synthesis of (-)-Pyrenophorol accomplished from cheaply available starting material, easily work-up procedures and reduction of cost in industrial process were major advantages of this route.

Synthesis of chalcone incorporated quinazoline derivatives as anticancer agents.

A series of ten novel chalcone incorporated quinazoline derivatives (11a-11j) were designed and synthesized. All the synthesized compounds were evaluated for their anticancer activities against four human cancer cell lines (A549, HT-29, MCF-7 and A375). Among them, four compounds, 11f, 11g, 11i and 11j showed more potent anticancer activity than the control drug, Combretastatin - A4.