Targeting the tumor microenvironment through the design and synthesis of potent, small-molecule, anticancer agents.

Abstract

Targeting the vascular network that supplies a tumor with oxygen and nutrients is a viable methodology for the treatment of cancer. With the discovery of the combretastatin extended family of compounds in the late 1970's and early 80's, there has been an accelerated interest in vascular targeting as a possible cancer treatment methodology. Two natural products, combretastatin A-1 (CA1) and combretastatin A-4 (CA4) interfere with the tubulin-microtubule protein system in the endothelial cells lining tumor vasculature, ultimately resulting in vessel damage. A new class of compounds shares similar functional group motifs and structural orientations to CA4, but is based on a benzosuberene core structure. These benzosuberene analogues incorporate a [6,7] fused ring system with an aryl ring attached at the 5-position. The initial discovery in the Pinney Research Group of the benzosuberene lead compound 1-hydroxy-2-methoxy-5-(3',4',5'-trimethoxyphenyl)benzocyclohept-5-ene 1, has led to research focused on the development of an efficient strategy for synthesizing [6,7] fused ring systems and the preparation of new, diversely functionalized benzosuberene analogues. New derivatives include regioisomeric incorporations of methoxy and hydroxy groups, along with the inclusion of nitro, amine, and halogen substituents. Bioreductively activated prodrug triggers, as well as [6,8] and [5,7] fused ring systems are also included in the library of compounds developed. Initial biological evaluation of these benzosuberene compounds provide interesting results. These compounds were evaluated for cytotoxicity against three human cancer cell lines, and for their ability to inhibit the assembly of tubulin into microtubules. Among the library of compounds screened, several analogues were discovered that are comparable in activity to CA4 and CA1. For example, 1,2-dihydroxy-5-(3',4',5'-trimethoxyphenyl)-benzosuber-5-ene 20 and 1,2-dimethoxy-5-(3',4',5'-trimethoxyphenyl)-benzosuber-5-ene 22 are strongly cytotoxic against the NCI-H460 human cell line (GI50 = 0.410 and 0.479 μM respectively). Collectively, the structure-activity relationship (SAR) knowledge gained from these compounds will guide the design of new benzosuberene-based anticancer agents.