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Caracasine acid (CA) is an ent-3,4-seco-kaurene isolated from the plant Croton micans. Decreased cancer cell lines viability was reported upon CA treatment. The present study aimed to investigate the mechanism of CA induced cytotoxicity using two human cell lines, Jurkat E6.1 (human cell T lymphoma) and HL-60 (human acute promyelocytic leukemia). Significant increases of apoptotic cell death markers upon CA treatment were observed: annexin-V positiveness, potential mitochondrial disturbances, cell cycle changes, caspase activation, and CD95 expression. These effects were not detected in normal lymphocytes. CA induced the appearance of Bax, cleaved caspase 3, and cytochrome c release in Jurkat cells, and cleaved caspase 3 and phosphorylated p53 in HL60 cells. Likewise, downregulation of anti-apoptotic proteins such as Bcl-x (Jurkat), Bcl-2, and XIAP (HL60) was observed with CA treatment. Both pathways, intrinsic and extrinsic were activated when cell lines were treated with CA. NF-κB p65 inhibition was observed in Jurkat cells and cell differentiation in HL-60 cells. CA could be a potential leader compound for the development of new drugs for leukemia treatment in humans., (Copyright © 2019 Elsevier B.V. All rights reserved.)

A series of caracasine acid (1) derivatives were synthesized and evaluated for their in vitro cytotoxicity on human cancer-derived cell lines MCF-7 and PC-3, as well as for other activities such as antibacterial, antileishmanial and antitrypanosomal activity. Compound 1 was more effective than any of its derivatives against tested human cancer cell lines. PC-3 cells were more sensitive than MCF-7 to all compounds, particularly the methyl ester (2), the amide (9) and the epoxide (10). The evaluation of antiparasitic activity revealed that ester derivatives (2-8) and the amide derivative (9) were the most effective antileishmanial and antitrypanosomal compounds, even though their effect on Trypanosoma cruzi was modest. Finally, compound 1 and the derivatives evidenced a broad spectrum of antibacterial activity, as assayed against Gram-positive and Gram-negative bacteria., (Copyright © 2015 Elsevier Ltd. All rights reserved.)