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Antitumor compounds based on a natural product consensus pharmacophore.

ABSTRACT: We report the design and highly enantioselective synthesis of a potent analogue of the spliceosome inhibitor FR901464, based on a non-natural product scaffold. The design of this compound was facilitated by a pharmacophore hypothesis that assumed key interaction types that are common to FR901464 and an otherwise unrelated natural product (pladienolide). The synthesis allows for the preparation of numerous novel analogues. We present results on the in vitro activity for this compound against several tumor cell lines.

SUBMITTER: Lagisetti C

PROVIDER: S-EPMC2701350 | biostudies-literature | 2008 Oct

REPOSITORIES: biostudies-literature

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Antitumor compounds based on a natural product consensus pharmacophore.

Lagisetti Chandraiah C Pourpak Alan A Jiang Qin Q Cui Xiaoli X Goronga Tinopiwa T Morris Stephan W SW Webb Thomas R TR

Journal of medicinal chemistry 20080913 19

We report the design and highly enantioselective synthesis of a potent analogue of the spliceosome inhibitor FR901464, based on a non-natural product scaffold. The design of this compound was facilitated by a pharmacophore hypothesis that assumed key interaction types that are common to FR901464 and an otherwise unrelated natural product (pladienolide). The synthesis allows for the preparation of numerous novel analogues. We present results on the in vitro activity for this compound against seve ...[more]

PMID: 18788726

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Project description:Malaria, caused by Plasmodium parasites, continues to be a devastating global health issue. Despite a decline in malaria related deaths over the last decade, overall progress has plateaued. Key challenges to malaria prevention and control include the lack of a broadly effective vaccine and parasite drug resistance, including to the current gold standard artemisinin combination therapies (ACTs). New drugs with unique modes of action are therefore a priority for both the treatment and prevention of malaria. Unlike treatment drugs which need to kill parasites quickly to reduce or prevent clinical symptoms, compounds that kill parasites more slowly may be an option for malaria prevention. Natural products and natural product derived compounds have historically been an excellent source of antimalarial drugs, including the artemisinin component of ACTs. In this study, 424 natural product derived compounds were screened for in vitro activity against P. falciparum in assays designed to detect slow action activity, with 46 hit compounds identified as having >50% inhibition at 10 μM. Dose response assays revealed nine compounds with submicromolar activity, with slow action activity confirmed for two compounds, alstonine and himbeline (50% inhibitory concentration (IC50) 0.17 and 0.58 μM, respectively). Both compounds displayed >140-fold better activity against P. falciparum versus two human cell lines (Selectivity Index (SI) >1,111 and > 144, respectively). Importantly, P. falciparum multi-drug resistant lines showed no cross-resistance to alstonine or himbeline, with some resistant lines being more sensitive to these two compounds compared to the drug sensitive line. In addition, alstonine displayed cross-species activity against the zoonotic species, P. knowelsi (IC50 ~1 μM). Outcomes of this study provide a starting point for further investigations into these compounds as antiplasmodial drug candidates and the investigation of their molecular targets.

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Antitumor compounds based on a natural product consensus pharmacophore.

Publications

Antitumor compounds based on a natural product consensus pharmacophore.

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