New (S)-verbenone-isoxazoline-1,3,4-thiadiazole hybrids: synthesis, anticancer activity and apoptosis-inducing effect.

Background: This study aimed to develop novel isoxazoline-1,3,4-thiadiazole hybrids from (S)-verbenone for potential anticancer treatment, particularly focusing on cytotoxic and apoptotic effects in hormone-sensitive MCF-7 and triple-negative MDA-MB-231 breast cancer cells. Methods & results: (S)-verbenone was used to synthesize hybrids through 1,3-dipolar cycloaddition, followed by thorough characterization. The compounds were screened across cancer cell lines, showing significant anticancer effects. Compound 8b notably induced apoptosis via the caspase-3/7 pathway and cell cycle arrest, displaying noteworthy cytotoxicity against MCF-7 and MDA-MB-231 cells. Conclusion: These findings underscore the potential of (S)-verbenone isoxazoline-1,3,4-thiadiazole derivatives for breast cancer therapy due to their remarkable apoptotic activity. This study highlights a promising avenue for advancing breast cancer treatment using these derivatives, founded on (S)-verbenone, showcasing their distinct potential for inducing apoptosis.

Cytotoxic and apoptotic effects of some (R)-carvone-isoxazoline derivatives on human fibrosarcoma and carcinoma cells: experimental evaluation for cytotoxicity, molecular docking and molecular dynamics studies.

This study aimed to analyze the cytotoxic and apoptotic effects of isoxazoline derivatives with monoterpene scaffold 9a-e in HT-1080 fibrosarcoma, MCF-7, and MDA-MB-231 breast carcinoma, and A-549 lung carcinoma. The cytotoxic effects data revealed that compounds 9a-e generally induced significant cell growth inhibition in all cell lines, with IC50 ranging from 10 to 30 µM. However, for compounds 9c and 9e, the IC50 reached a value of 100 µM in HT-1080 cells. Compounds 9a, 9b, and 9d could induce apoptosis in HT-1080 cells as demonstrated by Annexin-V labeling and Caspase-3/7 activity. The apoptotic effect was accompanied by cell cycle arrest in the S phase. Molecular docking and molecular dynamics confirmed the empirical assay results and confirmed the stability of the complex with the inhibition of the anti-apoptotic protein, leading to cancer cell death. Overall, these data suggest that the proposed isoxazoline derivatives may be potential candidates for further investigation to evaluate their efficacy and optimal use in cancer treatment.Communicated by Ramaswamy H. Sarma.

New 1,3,4-thiadiazoles derivatives: synthesis, antiproliferative activity, molecular docking and molecular dynamics.

Aim: A series of 1,3,4-thiadiazole himachalene hybrids were prepared from the treatment of a himachalen-4-one thiosemicarbazone derivative with N-aryl-C-ethoxycarbonyl-nitrilimines and diarylnitrilimines via a 1,3-dipolar cycloaddition reaction. Materials & methods: The structures were confirmed by NMR, IR and high-resolution mass spectroscopy (HRMS). Results & conclusion: The newly synthesized hybrid compounds were tested for their in vitro antitumor activities against a panel of cancer cell lines including fibrosarcoma (HT-1080), lung carcinoma (A-549) and breast carcinoma (MCF-7 and MDA-MB-231). Among the tested products, 4a showed excellent activity against the HT-1080 and MCF-7 cell lines with IC50 values of 11.18 ± 0.69 and 12.38 ± 0.63 µm, comparable to that of the reference drug. Docking results confirmed that the active inhibitors were well accumulated in the mushroom tyrosinase active site. Flow cytometry analysis indicated that hybrid 4a induced apoptosis and cell cycle arrest in the G0/G1 phase. Molecular modeling studies affirmed the intercalative binding of compound 4a in the active site.

Newly synthesized (R)-carvone-derived 1,2,3-triazoles: structural, mechanistic, cytotoxic and molecular docking studies.

In the current study, natural (R)-carvone was used as starting material for the efficient synthesis of several 1,2,3-triazole derivatives. The produced products were obtained in good yields and characterized by 1H and 13C NMR and HRMS analysis. The newly synthesized monoterpenic 1,2,3-triazole 4 and derivatives were analyzed by viability tests (MTT) for their cytotoxic activity against three human cancer cells. Product 5 showed a medium antitumor activity, for which the IC50 values against selected cells HT-1080, A-549 and MCF-7 were 29.25 µM, 31.62 µM and 26.02 µM, respectively. The regioselectivity of the condensation reaction and the molecular structure of the title compounds were determined by Density Functional Theory (DFT) using B3LYP calculations at 6-311 + G(d,p) level. The orbitals HOMO and LUMO were studied to determine the electronic properties of the synthesized compounds. In addition, the global reactivity indices were used to explain the regioselectivity for the formation of compound 6, and the theoretical results agree well with the experimental results. Molecular docking and molecular dynamics confirmed the empirical test results and confirmed the stability of the complex during inhibition of the anti-apoptotic protein for killing cancer cells. Communicated by Ramaswamy H. Sarma.

Thiazolidinone-linked1,2,3-triazoles with monoterpenic skeleton as new potential anticancer agents: Design, synthesis and molecular docking studies.

A novel series of 1,2,3-triazole-thiazolidinone-carvone hybrid compounds has been designed and synthesized using the copper-catalyzed Huisgen azide-alkyne 1,3-dipolar cycloaddition (CuAAC) process based on (R)-Carvone-O-propargylated 5-hydroxybenzylidene-thiazolidin-4-one derivative as starting material. All compounds were characterized and identified based on their NMR and HRMS spectroscopic data. HMBC correlations confirm that under the CuAAC reaction conditions, only the 1,4-disubstituted triazole regioisomers were formed. The targeted 1,2,3-triazole-thiazolidinone-carvone hybrids and their precursors were evaluated for their cytotoxic activity against four human cancer cell lines, including fibrosarcoma (HT-1080), lung carcinoma (A-549), and breast carcinoma (MCF-7 and MDA-MB-231). The obtained data showed that most of these compounds have moderate anti-proliferative activity with IC50 values between 15.04 ± 0.71 and 42.22 ± 1.20 µM. The mechanism of action of the most active compounds 14e and 14f suggested that they induce apoptosis through caspase-3/7 activation, and the compound 14e elicited S-phase arrest, while compound 14f evoked G2/M phase blockade. The molecular docking confirmed that compounds 14e and 14f were nicely bonded with caspace-3 leading up to stable protein-ligand complexes.

Design, Hemiysnthesis, crystal structure and anticancer activity of 1, 2, 3-triazoles derivatives of totarol.

A new series of diverse triazoles linked to the hydroxyl group of totarol were synthesized using click chemistry approach. The structures of these compounds were elucidated by HRMS, IR and NMR spectroscopy. The structure of compound 3 g was also confirmed by x-ray single crystal diffraction. The cytotoxicity of these compounds was evaluated by the MTT method against four cancer cell lines, including fibrosarcoma HT-1080, lung carcinoma A-549 and breast adenocarcinoma (MDA-MB-231 and MCF-7), and the results indicated that all compounds showed weak to moderate activities against all cancer cell lines with IC50 values ranging from 14.44 to 46.25 µM. On the basis of our research the structure-activity relationships (SAR) of these compounds were discussed. This work provides some important hints for further structural modification of totarol towards developing novel and highly effective anticancer drugs respectively. It is interesting to note that compound 3 g indicated a very significant cytotoxicity against HT-1080 and A-549 cell lines. The molecular docking showed that compound 3 g activated the caspase-3 and inhibited tubulin by forming stable protein-ligand complexes.

Crystal structure of (4bS,8aR)-1-isopropyl-4b,8,8-trimethyl-7-oxo-4b,7,8,8a,9,10-hexa-hydro-phenanthren-2-yl acetate.

The title compound, C22H28O3, was prepared by a direct acetyl-ation reaction of naturally occurring totarolenone. The mol-ecule contains three fused rings, which exhibit different conformations. The central ring has a half-chair conformation, while the non-aromatic oxo-substituted ring has a screw-boat conformation. In the crystal, mol-ecules are linked by C-H⋯O hydrogen bonds and C-H⋯π inter-actions, forming sheets parallel to the bc plane. The carbonyl O atoms and the C atom at the 6-position of the cyclo-hexene ring are each disordered over two sets of sites with major occupancy components of 0.63 (7) and 0.793 (14), respectively.

Crystal structure of 2-isopropyl-4-meth-oxy-5-methyl-phenyl 4-methyl-benzene-sulfonate.

The title compound, C18H22O4S, an hemisynthetic product, was obtained by the tosyl-ation reaction of the naturally occurring meroterpene p-meth-oxy-thymol. The mol-ecule comprises a tetra-substitued phenyl ring linked to a toluene-sulfonate through one of its O atoms. In the crystal, C-H⋯O and C-H⋯π inter-actions link the mol-ecules, forming a three-dimensional network.