RARs belong to a super family of nuclear receptors that act as transcription factors. Retinoids bind to RAR subtypes α, β, γ; and RXR subtypes α, β, γ and modulate the activation of these important transcription factors. Retinoids play a vital role in a variety of dermatological disorders and neoplastic diseases due to their effects on cell differentiation, proliferation, and variety of cancer cell lines.
Currently available retinoids exhibit some preference for receptor subtypes but none are considered truly subtype selective and all associated with serious toxicity. A goal in the present research was to synthesize novel RAR compounds with high affinity and improved selectivity for RAR subtypes. This project used a pharmacophoric model, molecular modeling and docking studies, SAR data and structure-based design approaches to design several series of potential RAR ligands.*
Three scaffoldings, namely, tetrahydrobenzoquinolinone (TBQ), chromone and trialkylsilyl acetylenic nuclei, were used to prepare structurally diverse RAR ligands. Well known reactions including Wittigs, Wadsworth-Horner-Emmons, Sonogashira, Friedel-Craft, and DCC coupling were used extensively to provide the target compounds. Molecules selected in modeling studies as possible RAR ligands were synthesized and tested in competitive binding experiments using [3H]-ATRA as the radioligand. This study investigates diverse group of scaffolds ranging from bulky polycyclic heteroaromatic systems (TBQ) to simple aliphatic nuclei. Compounds were identified with moderate affinity for RARs that may exhibit a small degree of receptor selectivity. Lead modification approaches were utilized to alter the structure to provide higher affinity, more selective ligands.*
Based on the limited number of compounds reported herein it appears that several molecular properties should be considered in the design of future ligands. Hence the pharmacophoric model for RAR ligands should be revised to include: (a) IAD—Optimal range of 12.5–15.5 Å. (b) Aliphatic groups in Region A. (c) Planarity and/or linearity especially in Region B. (d) Conjugation between Regions A and C.
The molecules reported herein would be used as leads for the design of higher affinity, more subtype selective RAR ligands in future. The factors described above will be considered in the design of the new RAR ligands.
*Please refer to dissertation for diagrams.