Optimization of antitumor modulators of pre-mRNA splicing.

The spliceosome regulates pre-mRNA splicing, which is a critical process in normal mammalian cells. Recently, recurrent mutations in numerous spliceosomal proteins have been associated with a number of cancers. Previously, natural product antitumor agents have been shown to interact with one of the proteins that is subject to recurrent mutations (SF3B1).

Radiosynthesis of antitumor spliceosome modulators.

A set of novel antitumor agents (the sudemycins) has recently been described that are analogs of the natural product FR901464. We report the radiosynthesis of two of these antitumor drug lead compounds, using a three step procedure: (1) ester hydrolysis, (2) Lindlar's catalyst/tritium gas to give a (S,Z)-4-acetoxypent-2-enoic acid derivative, and finally (3) amide bond formation. These labeled analogs are useful in developing a better understanding of the pharmacological properties of this new class of therapeutic lead compounds.

Synthetic mRNA splicing modulator compounds with in vivo antitumor activity.

We report our progress on the development of new synthetic anticancer lead compounds that modulate the splicing of mRNA. We also report the synthesis and evaluation of new biologically active ester and carbamate analogues. Further, we describe initial animal studies demonstrating the antitumor efficacy of compound 5 in vivo.

Modulation of a Schistosoma mansoni multidrug transporter by the antischistosomal drug praziquantel.

P-glycoprotein (Pgp) is an ATP-dependent efflux pump involved in transport of xenobiotics from cells that, when overexpressed, can mediate multidrug resistance in mammalian cells. Pgp may be a candidate target for new anthelmintics, as it plays critical roles in normal cell physiology, in removal of drugs from cells, and potentially in the development of drug resistance. Schistosomes are parasitic flatworms that cause schistosomiasis, which affects hundreds of millions of people worldwide.

Towards an understanding of the mechanism of action of praziquantel.

Although praziquantel (PZQ) has been used to treat schistosomiasis for over 20 years its mechanism of action remains unknown. We have developed an assay based on the transcriptional response of Schistosoma mansoni PR-1 to heat shock to confirm that while 6-week post-infection (p.i.

Antitumor compounds based on a natural product consensus pharmacophore.

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.