Antitumor Agents. 284. New Desmosdumotin B Analogues with Bicyclic B-Ring as Cytotoxic and Antitubulin Agents

Abstract

We previously reported that the biological activity of analogues of desmosdumotin B (1) was dramatically changed depending on the B-ring system. A naphthalene B-ring analogue 3 exerted potent in vitro activity against a diverse panel of human tumor cell lines with GI50 values of 0.8–2.1 μM. In contrast, 1-analogues with a phenyl B-ring showed unique selective activity against P-glycoprotein (P-gp) overexpressing multidrug resistance cell line. We have now prepared and evaluated 1-analogues with bicyclic or tricyclic aromatic B-ring systems as in vitro inhibitors of human cancer cell line proliferation. Among all synthesized derivatives, 21 with a benzo[b]thiophenyl B-ring was highly active, with GI50 values of 0.06–0.16 μM, and this activity was not influenced by overexpression of P-gp. Furthermore, 21 inhibited tubulin assembly in vitro with an IC 50 value of 2.0 μM and colchicine binding by 78% as well as cellular microtubule polymerization and spindle formation.

The Tubulin Colchicine Domain: a Molecular Modeling Perspective

“…Nguyen and colleagues established that one hydrogen bond acceptor, two hydrophobic centers, and a planar group were the minimum features required for drug activity. This proposed pharmacophore model was taken into account by several other research groups [62,63] as a reference or starting point for the development of new pharmacophore hypotheses. The relevance of this model was also confirmed in other publications that described the selected features for the authors' pharmacophore models as being chemically and geometrically very similar to those proposed by Nguyen et al [64][65][66] …”

Development of a Novel Class of Tubulin Inhibitor from Desmosdumotin B with a Hydroxylated Bicyclic B-Ring

“…Compounds 13, 17, 18 , and 20 were previously synthesized. 15 The required benzo[ b ]thiophene aldehydes 24–27 were constructed as shown in Scheme 2. The condensation of p -, m -, and o -methoxybenzenethiols ( 32–34 ) with α -chloro ketone, followed by cyclization with polyphosphoric acid at 100 °C, afforded 5-methoxy-3-methylbenzo[ b ]thiophenes ( 35 ) from 32 , 4- and 6-methoxy derivatives ( 36 and 37 ) from 33 , and the 7-methoxy derivative ( 38 ) from 34 .…”

“…Importantly, none of the analogues were P-gp substrates, and thus, they may be potentially effective against MDR tumors. 15 …”

Synthesis of novel spin-labeled derivatives of 5-FU as potential antineoplastic agents

“…Antiproliferative activity was determined by the sulfo-rhodamine B (SRB) colorimetric assay as previously described (Nakagawa-Goto et al , 2011). In brief, cells (3–5 × 10 3 cells/well) were seeded in 96-well plates filled with culture medium containing various concentrations of sample and incubated for 72 h. At the end of the exposure period, cells were fixed with cold 50 % trichloroacetic acid followed by staining with 0.04 % SRB (Sigma Chemical Co.).…”