The repositioning of efavirenz within the drug binding pocket of the mutant RT, together with conformational rearrangements in the protein, could represent a general mechanism whereby certain second-generation non-nucleoside inhibitors are able to reduce the effect of drug-resistance mutations on binding potency.

A series of biaryl acids has been reported that inhibit both HIV-1 and HIV-2 RT, although these appear not to bind at the NNRTI site (4). NNRTIs such as nevirapine generally act as noncompetitive inhibitors of HIV-1 RT with respect to substrates (5), binding in a pocket some 10 Å from the polymerase active site (6 -8). The NNRTI binding site is contained largely within the p66 subunit of the RT heterodimer with only a few residues at the periphery of the site being contributed by the p51 subunit. The mechanism of inhibition for NNRTIs has been shown to be via a distortion of the key catalytic active site aspartyl residues (9). One series of NNRTIs previously described is the phenylethylthiazoylthiourea (PETT) series that have been shown to have potent activity against both HIV-1 virus and it's RT (10 -13). Further PETT analogues have been designed using information from the three-dimensional structure of HIV-1 RT (14 -16). In this work we report structural and biochemical studies for two members of this series referred to as PETT-1 and PETT-2 (Scheme 1).Most NNRTIs rapidly select for drug-resistant HIV-1 strains, both in tissue culture and in clinical studies, which has largely precluded their use as monotherapy (17). In contrast to the "first-generation" drugs, nevirapine and delavirdine, the so-called "second-generation" NNRTI drug, efavirenz, demonstrates resilience to the effects of certain common resistance mutations (18). However resistance to such compounds is * This work was supported by the European Commission (Project PL96-2161). The Oxford Centre for Molecular Sciences is supported by the Biotechnology and Biological Sciences Research Council, Medical Research Council, and Engineering and Physical Sciences Research Council. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.The atomic coordinates and structure factors (codes 1dtq and 1dtqsf and 1dtt and 1dttsf)

Multidrug resistance mediated by P-glycoprotein (Pgp) or multidrug-resistance-associated protein (MRP) remains a major obstacle for successful treatment of cancer. Inhibition of Pgp and MRP transport is important for high efficacy of anticancer drugs. While several Pgp inhibitors have entered clinical trials, the development of specific MRP1 inhibitors is still in its infancy. In our screening program, we have identified a pyrrolopyrimidine (4) as a novel and selective MRP1 inhibitor. Subsequent SAR work on the 4-position of the template revealed the phenethylpiperazine side chain as a potent replacement of the benzylthio group of the lead molecule. Introduction of groups at the 2-position seems to have no detrimental effect on activity. Modifications to the nitrile group at the 7-position resulted in the identification of analogues with groups, such as amides, with superior pharmacokinetic profiles. In vivo efficacy has been demonstrated by xenograft studies on selected compounds.

A series of substituted angular benzophenazines were prepared using a new synthetic route via a novel regiocontrolled condensation of 1,2-naphthoquinones and 2,3-diaminobenzoic acids. The synthesis and biological activity of this new series of substituted 8,9-benzo[a]phenazine carboxamide systems are described. The analogues were evaluated against the H69 parental human small cell lung carcinoma cell line and H69/LX4 resistant cell line which overexpresses P-glycoprotein. Selected analogues were evaluated against the COR-L23 parental human non small cell lung carcinoma cell line and the COR-L23/R resistant cell line which overexpresses multidrug resistance protein. This series of novel angular benzophenazines were potent cytotoxic agents in these cell lines and may be able to circumvent multidrug resistance mechanisms which result in the lack of efficacy of many drugs in cancer chemotherapy. These compounds show dual inhibition of topoisomerase I and topoisomerase II and thus target two key enzymes responsible for the topology of DNA that are active at different points in the cell cycle. The introduction of chirality into the carboxamide side chain of these novel benzophenazine carboxamides has resulted in the discovery of a potent enantiospecific series of cytotoxic agents, exemplified by 4-methoxy-benzo[a]phenazine-11-carboxylic acid (2-(dimethylamino)-1-(R)-methyl-ethyl)-amide, XR11576 ((R)-4j' '). In vivo activity has been demonstrated for 4-methoxy-benzo[a]phenazine-11-carboxylic acid (2-(dimethylamino)-1-(R)-methyl-ethyl)-amide, XR11576, after intravenous administration to female mice, and this compound has been selected as a development candidate for further evaluation.