Abstract #5562: Discovery of tetrahydroisoquinoline based microtubule disrupting agents with in vivo anti-angiogenic activity

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO Previously, we developed a series of steroidal derivatives as dual inhibitors of cancer cell proliferation and angiogenesis and have now explored whether SAR from this work could be used to design non-steroidal compounds with a similar activity profile. Such compounds possess considerable therapeutic potential, as demonstrated by the successful clinical application of angiogenesis inhibitors in combination with cytotoxic agents. Tetrahydroisoquinolines (THIQs) and dihydroisoquinolinones (DHIQs) were chosen as prototypical mimics of the steroidal A,B-ring system. Functionalisation of the THIQ and DHIQ cores at N -2 with H-bond acceptor substituted benzyl, benzoyl and benzenesulfonyl groups was intended to mimic the D-ring bearing the motif requisite for enhanced activity in the steroidal series. In both cases 3\#8242;-methoxy substitution was preferred, with benzyl and benzoyl substitution proving optimal for the respective THIQ 1 and DHIQ 2 series. First generation compounds displayed low micromolar activity against the proliferation of DU-145 prostate cancer cells. Further exploration of the THIQ series 1 confirmed that all compounds bereft of any of the three key motifs requisite for activity in the steroidal series displayed much lower activity. Replacement of the H-bond accepting methoxyl group with a range of ethers and esters defined the steric parameters for acceptable substitution and afforded a 2-fold gain in activity (3\#8242;-ethoxy derivative GI50 1.1 \#956;M). Substitution of the methoxyl group with alternate H-bond acceptors delivered a range of other active leads (e.g. 3-acyl GI50 1.8 \#956;M). Investigations on polysubstituted N -benzyl derivatives delivered a further enhancement in activity (3\#8242;,4\#8242;,5\#8242;-MeO GI50 297 nM). Biological profiling showed that, as in the steroidal series, such compounds destabilise the Taxol stimulated polymerisation of tubulin in vitro . Anti-proliferative effects of the THIQ derivatives against both wild type MCF-7 breast cancer cells and the resistant MCF-7DOX cell line were demonstrated, thus indicating the potential of these compounds for the treatment of resistant tumors. Inhibition of HUVEC cell proliferation in vitro indicated that these compounds were likely to possess anti-angiogenic activity. An in vivo mouse matrigel plug assay was used to confirm the compounds\#8217; anti-angiogenic activity, with oral administration of the 3\#8242;,4\#8242;,5\#8242;-MeO THIQ derivative revealing the non-steroidal compound to be equipotent to the best steroidal compounds at similar doses. Scaffolds exemplified here thus have considerable potential for the discovery and development of novel anticancer agents. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5562.