The first part of the Conference will present a novel series of combretastatin A-4 heterocyclic analogues. Target compounds were prepared by replacement of the B ring with indole, benzofurane or benzothiophene, attached at the C2 position. These compounds were evaluated for their abilities to inhibit tubulin assembly: derivative cis3b, having a benzothiophene, showed an activity similar to those of colchicine or deoxypodophyllotoxine. The antiproliferative and antimitotic properties of cis3b against keratinocyte cancer cell lines were also evaluated and the intracellular organization of microtubules in the cells after treatment with both stereoisomers of 3b was also determined, using confocal microscopy.
The second part of the Conference will present a novel class of P-gp/ABCB1 ligands, known as reversins. Na-Boc-L-Asp(OBn)-L-Lys(Z)-OtBu (reversin 121), an inhibitor of the P-gp ABC transporter, was used to conceive our compounds inhibiting the drug efflux occurring through the Hoechst 33342 and daunorubicin transport sites of P-gp, respectively Hand R sites. ABC (ATP-binding cassette) transporters are involved in several genetic diseases and are responsible for the cellular multidrug resistance phenotype encountered during chemotherapeutic treatments against cancer and viral diseases. In such a context, they represent a serious threat, since cancer cells overexpress them to reduce drug concentration below its cytotoxic threshold. The most potent compound behaved as a noncompetitive inhibitor for both the R and H drug-transport sites of P-gp, which limits the possibility for such an inhibitor to be itself transported by P-gp.
Abstract (.pdf)