Development of New Retinoids for Treatment of Epithelial Cancer

Research Article

Austin J Anal Pharm Chem. 2017; 4(3): 1089.

Development of New Retinoids for Treatment of Epithelial Cancer

Mohanraj SM¹* and McMurry JE²

¹PolyMicrospheres, Division of Vasmo Inc., Indianapolis, IN, USA

²Baker Laboratory, Department of Chemistry, Cornell University, Ithaca, NY, USA

*Corresponding author: Mohanraj SM [1], PolyMicrospheres, Division of Vasmo Inc., 4101 East 30th Street, Indianapolis, IN 46218, USA

Received: July 29, 2017; Accepted: August 23, 2017; Published: August 30, 2017

Abstract

A new series of fifteen retinoids based on the dimethyltetralin ring system has been developed for evaluation as therapeutic agents in the treatment of epithelial cancer and other skin diseases. Four types of retinoids (A-D) were synthesized in which various side-chain double bonds are rigidly held in specific conformations, and their structure-activity relationships were investigated. Most of the new retinoids exhibit high activity in reversing keratinization in hamster tracheal organ culture. Retinoids 10b, 18a, and 18b show ED50(M) values in the (3-5)x10-11 range, and are promising candidates for the prevention and treatment of epithelial cancer. Among the most active retinoids, the 9E isomers are 40-60 times more active than the corresponding 9Z isomers.

Keywords: Aromatic retinoids; Cis-and trans-retinoids

Introduction

The retinoids, a large class of polyunsaturated diterpenes structurally related to vitamin A, have aroused much interest because of their diverse biological properties [2]. For example, vitamin A itself is important in promoting general growth, in regulating proliferation and differentiation of epithelial tissues, and in maintaining visual function and reproduction. The effect of vitamin A on epithelial tissues [3] has attracted much attention because vitamin A deficiency leads to hyperkeratosis of the skin and to metaplastic changes in the epithelia of gastrointestinal, respiratory, and urogenital tracts.

A number of synthetic retinoids have been reported to be extremely effective in the treatment of various types of keratinization disorders [3]. In addition, some synthetic retinoids exert antiinflammatory effects and seem to possess immunomodulatory properties [4], influencing dermal components such as lymphocytes and macrophages [2]. Retinoids have also been applied to the treatment of skin diseases like psoriasis and severe acne [3,5], and seem to interfere with the growth of oncogenic viruses and virus induced cancer [6].

One drawback to the use of known retinoids, both natural and synthetic, for the treatment of epithelial cancer and other keratinization disorders is that serious side effects often occur [7]. When given in high doses, retinoid levels rise in blood, tissues and liver, causing toxic effects known collectively as hypervitaminosis A syndrome. Though many retinoids have been synthesized, it still remains to the chemist to design and synthesize further structural variations of the retinoid skeleton that are more potent and less toxic, have improved pharmacokinetic properties, and are site specific.

The retinoic acid molecule is composed of three building units – a nonpolar cyclic end group, a polyene chain and a polar head group. Although it is relatively easy to probe structure-activity relationships involving the cyclic end group and polar head group, side-chain effects on biological activity are more difficult to study. The conformational flexibility of the side chain makes it possible for retinoids to adopt a large number of conformations, some of which are biologically active while others are inactive.

In order to probe the effects of side-chain conformation on biological activity, we decided to synthesize four types of new retinoids containing dimethyltetralin end groups (A-D in Chart 1), in which various double bonds are rigidly held in specific conformations. Few related structures with tetramethyltetralin end groups have been reported [8]. Our hope was to find a structure-activity relationship between side-chain conformation and activity that might allow chemists to design more suitable therapeutic agents. Bicyclic type A analogs have the 5,6 and 7,8 double bonds of the retinoic acid locked into an s-cis conformation without disturbing the rest of the molecule, while tricyclic analogs of types B–D have additional constraints on double bond geometry imposed by introduction of a third ring. In this paper, we report the synthesis and biological activity of these new retinoids and their 9Z isomers.