1) Synthesis of flexible heteroarotinoids for anti-cancer activity and metal free synthetic approaches to bioactive compounds

Abstract

The first project of this work involved the synthesis flexible heteroarotinoids for anti-cancer activity. Flexible Heteroarotinoids (Flex-Hets) are a class of substituted di-aryl compounds that exhibit potent anti-cancer activity without toxicity. Previously, our group developed a sulfur containing heteroarotinoid S-Het-A2 (NSC 721689), exhibited promising activity against 62 different cancer cell lines at micromolar concentration with excellent differentiation between normal and cancer cells. The primary goal of this work is to improve the activity of the lead compound S-Het-A2. To achieve this, we synthesized 42 modified heteroarotinoids and they were tested against human A2780 ovarian cancer cell line.

Altering the linker unit: The thiourea unit in S-Het-A2 was replaced by acrylamide, N-benzylacetamide and thiazoline. Nitro- substitution on the ring B aryl group caused similar activity compared to S-Het-A2 for acrylamide linker. When N-benzylacetamide and thiazoline were used as linker, the compounds were completely devoid of activity.

Nitrogen containing heteroarotinoids: The sulfur atom in the cyclohexyl ring in S-Het-A2 was replaced by nitrogen. Nitrogen heteroarotinods with a carbonyl group at C3 of ring A exhibited greater activity than the S-Het-A2, whereas a hydroxyl at C3 and Flex-Hets without a gem-dimethyl next to nitrogen atom trimmed the activity to a large extent.

Tethering bioactive motifs to S-Het-A2 rings: A fragment based approach was attempted by joining ring A and ring B of S-Het-A2 with bioactive compounds such as indole, quinoline, oxazoline, furfuryl and aspirin. None of these compounds exhibited even moderate activity. However, reducing the nitro group of S-Het-A2 to an amino group resulted in enhanced activity.

The second part of this work involved devising new methods for preparing biologically active compounds under metal free conditions. These methods are summarized below

Synthesis of isoquinolinones, naphthyridinones pyrazoloquinazolinones, pyrazolopyridopyrimid-inones and benzimidazoquinazolinones have been developed using an N-acylation - SNAr reaction sequence. The newly developed methods afforded better yields under milder reaction conditions compared to earlier reported methods.

The SNAr strategy was further extended to add enolates and amines to electron deficient vinylarenes. This method allowed enolates to add across unsubstituted and a-substituted electron deficient vinyl arenes.

An efficient, inexpensive approach to synthesis 1,3,4-oxadiazole was established using catalytic NH4Cl and also an efficient tandem reaction was designed to synthesize 4-chromanone using 20 mol% of bismuth(III) triflate.