Novel Bis-spiro-labdane type Diterpenes from Leonotis nepetifolia: Isolation, Semi-synthesis, and Evaluation of their Cytotoxic Activities

• Published in: Journal of molecular structure Vol. 1305; p. 137728
• Main Authors: Rao, Banoth Venkateswara, Swain, Sonam, Siva, Bandi, Priya, Telukuntla Sai, Alli, Vidya Jyothi, Jadav, Surender Singh, Jain, Nishant, Ramalingam, Vaikundamoorthy, Babu, K. Suresh
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 05.06.2024
• Subjects: Cytotoxicity; Isolation; Leonotis nepetifolia; Molecular docking; Nepetaefolinol derivatives; Isolation; Cytotoxicity; Leonotis nepetifolia; Nepetaefolinol derivatives; Molecular docking
• ISSN: 0022-2860; 1872-8014
• DOI: 10.1016/j.molstruc.2024.137728

•A novel bis-spiro labdane type diterpenoid nepetaefolinoside A (1).•Nepetifolinol (2) derivatives were synthesized.•Compound 15 displayed potent anticancer activity (IC50: 1.7 ± 0.34 µM) against Hela cell.•Compound 15 arrest the cell cycle progression at G2/M phase by upregulating the Cyclin B1 protein expression.•Docking studies of 15 showed strong binding affinity with Tubulin protein through hydrogen bond. Traditional medicinal plants offer huge opportunities to discover novel therapeutics against many diseases. Investigation into the chemical diversity of the traditional medicinal plant, Leonotis nepetifolia led to the identification of a novel bis-spiro labdane type diterpenoid, nepetaefolinoside A (1) along with eleven known compounds (2-12). Their structures were elucidated on the basis of 1D and 2D NMR techniques. Further, semi-synthetic derivatives of nepetaefolinol (2) were synthesized, and evaluated for their in vitro cytotoxicity along with the isolates against a panel of human cancer cell lines using SRB assay. The results clearly evidenced that most of the derivatives significantly inhibited the growth of cancer cell lines. Especially, compound 15 which is a synthetic derivative of compound 2 containing the acetylenic moiety displayed potent anticancer activity (IC50: 1.7 ± 0.34 µM) as compared with the parent molecule 2 (IC50: 54 ± 1.27 µM) and standard nocodazole (IC50: 5.3 ± 1.3 µM) against cervical cancer cell line (Hela). Flowcytometry analysis of 15 revealed that it induced apoptosis and arrested cell cycle in G2/M phase and further generates oxidative stress in HeLa. Mechanistic studies have shown that 15 induce tubulin depolymerization and arrest the cell cycle by upregulating the Cyclin B1 protein expression and inhibits the invasion and proliferation of HeLa cells. From the docking studies, it was observed that the compound 15 has strong binding affinity with the Tubulin protein through hydrogen bond interactions. Overall, the results demonstrated that compound 15 exhibited highest activity and found to be much more potent than the parent compound 2 as well as standard nocodazole. [Display omitted]