PubMed · 13086150
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T A HENRY. 1953. Alkaloids.. https://pubmed.ncbi.nlm.nih.gov/13086150/
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Sanguinarine (SA), a member of the benzo[c]phenanthridine alkaloids, is a potent anti-microbial agent with anti-inflammatory and anti-neoplastic properties. However, toxicity of the alkaloid severely limits its medical applications. Recent report by Williams et al. implicated rat hepatic cytochrome P450 (CYP) 1A2 as a likely modulator of SA toxicity. Indeed, the in vitro toxicity of SA in primary culture of rat hepatocytes and human hepatic cell line HepG2, demonstrated as lactate dehydrogenase leakage and metabolic capability (MTT assay), was diminished following induction of CYP1A by 2,3,7,8-tetrachlorodibenzo-p-dioxin, 3-methylcholanthrene, and beta-naphtoflavone. Using microsomes containing recombinant CYP1A1 or CYP1A2 we show that SA causes non-competitive inhibition of the former and competitive inhibition of the latter as assessed by ethoxyresorufin de-ethylation (EROD). In human hepatic microsomes SA exhibits competitive inhibition of EROD activity with apparent K(i) of 2 microM, a value identical to that observed for CYP1A2 inhibition in recombinant system. Pre-incubation of SA with human liver microsomes resulted in time-dependent, but not dose-dependent decline in EROD activity suggesting CYP1A2 inhibition is not mechanism based. SA also inhibits activity of NADPH:CYP reductase, an enzyme required for CYP activity, with IC(50) very similar to that observed for EROD inhibition. Tentative mechanism for CYP1A involvement in decreased in vitro SA toxicity is discussed.
We describe herein an evaluation of trypanocidal effects of the natural alkaloid piperine and twelve synthetic derivatives against epimastigote and amastigote forms of the protozoan parasite Trypanosoma cruzi, the causative agent of the incurable human disease, Chagas' disease. The results obtained point to piperine as a suitable template for the development of new drugs with trypanocidal activity.
Based on a common pharmacophore model and the hypothesis that the baccatin core of taxoids is a scaffold securing the proper orientation of the side chains, a bicyclic alkaloid scaffold was designed as a baccatin surrogate. Using this scaffold, two novel macrocyclic and open-chain 'taxoid-mimicking' compounds were synthesized. Two of these 'taxoid-mimics', 2 and 3, were found to possess cytotoxicity with micromolar level IC50 values against human breast cancer cell lines.