Hydrogen sulfide releasing enmein-type diterpenoid derivatives as apoptosis inducers through mitochondria-related pathways

• Published in: Bioorganic chemistry Vol. 82; pp. 192 - 203
• Main Authors: Xu, Fanxing, Gao, Xiang, Li, Haonan, Xu, Shengtao, Li, Xu, Hu, Xu, Li, Zhanlin, Xu, Jinyi, Hua, Huiming, Li, Dahong
• Format: Journal Article
• Language: English
• Published: SAN DIEGO Elsevier Inc 01.02.2019; Elsevier
• Subjects: Apoptosis; Biochemistry & Molecular Biology; Chemistry; Chemistry, Organic; Enmein-type diterpenoid; Hydrogen sulfide; Life Sciences & Biomedicine; Mitochondria-related pathway; Physical Sciences; Science & Technology; Enmein-type diterpenoid; Hydrogen sulfide; Mitochondria-related pathway; Apoptosis; GROWTH-INHIBITION; PACLITAXEL TAXOL(R); ANTIINFLAMMATORY DRUG; ORIDONIN-INDUCED APOPTOSIS; GINKGOLIDE-B; CELL-CYCLE ARREST; NATURAL ORIDONIN; ENT-KAURANE DITERPENOIDS; BIOLOGICAL EVALUATION; CYSTATHIONINE-BETA-SYNTHASE
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2018.10.002

[Display omitted] •Hybrids of enmein-type diterpenoids and hydrogen sulfide donors were synthesized.•Most derivatives exhibited potent antiproliferative activities with low IC50 values.•A1 showed excellent selectivity between human normal and tumor liver cells.•A1 induced apoptosis and arrest cell cycle at G1 phase in Bel-7402 cells.•A1 induced Bel-7402 cells apoptosis via the mitochondria-dependent pathway. In this study, we combined two enemin-type diterpenoid derivatives with two well-established hydrogen sulfide moieties via ester or different anhydride linkers, to search apoptosis inducing drug candidate capable of hydrogen sulfide generating. Therefore, a series of hybrids were synthesized and superior antiproliferative efficacy accompanied with enhanced selectivity was observed under extensive pharmacological evaluations. A standard methylene blue (MB+) method was applied to measure the capacity for the hydrogen sulfide generation of all the target derivatives. One particular molecule A1, which contained α-thioctic acid moiety for hydrogen sulfide donating, manifested more potent antiproliferative activity. It exerted inhibitory effects against Bel-7402, SGC-7901 and A549 cell lines with IC50 values of 2.16, 5.07 and 6.98 μM respectively. While it exacted relatively low effects over human normal cell lines L-02 and PBMC with IC50 values of 15.81 μM for the prior and 14.15 μM for the latter, and displayed better selectivity index (SI) than parent diterpenoids. A high dosage of H2S release was also recorded. Hence, A1 was most suitable for mechanistic exploration on account of both safety and efficacy. The ensuing biological assays revealed central role of apoptosis in A1’s mode of action for antiproliferative efficacy, which led to further confirmation of G1 phase cell cycle arrest, mitochondria membrane potential collapse and apoptotic activation in Bel-7402 cells. Further western blot assay on intrinsic mitochondria pathway unlocked intricate interplay among a series of apoptotic related proteins in which Bax, caspase-3 and cytochrome c went through up-regulation, while Bcl-2, Bcl-xL and procaspase-3 undergone down-regulation. In a nutshell, a hydrogen sulfide releasing hybrid A1 was synthesized and antiproliferative evaluation identified it to be a worthy drug candidate for future in depth study.