Synthesis of 4/5‐Deoxy‐4/5‐nucleobase Derivatives of 3‐O‐Methyl‐D‐chiro‐inositol as Potential Antiviral Agents

Abstract

Using D-pinitol (= 3-O-methyl-D-chiro-inositol) as starting material, a concise synthesis of 4/5-deoxy-4/5-nucleobase derivatives 11-19 has been achieved. The key intermediate 9 was obtained in good yield via an epoxidation from mono-methanesulfonate of D-pinitol. The process of opening of the epoxide ring in 9 by nucleobases appeared to be regioselective in presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). All the synthesized carbocyclic nucleosides were assayed against several viruses and tumors such as HIV-1, HSV-1, and HSV-2, and lung and bladder cancer. However, only compounds 14b, 14a, 16a, 16b, and 19 showed mild inhibitory effect against human lung cancer cell lines (PG) with IC50 values ranging from 50 to 100 microM, and the other compounds did not exhibit any significant antiviral activity or cytotoxicity even at concentrations up to 200 microM.

Pinitol targets nuclear factor-κB activation pathway leading to inhibition of gene products associated with proliferation, apoptosis, invasion, and angiogenesis

“…Our group, however, has shown that deletion of NF-nB (p65) abolishes the TNF-induced expression of COX-2 and cyclin D1 (46), indicating the critical requirement of NF-nB in the expression of these genes. The suppression of expression of various NF-nB regulated gene products examined here may explain the antitumor and antiviral properties of recently synthesized analogues of pinitol (7,47). We also found that this inositol potentiated the apoptotic effects of TNF and chemotherapeutic agents.…”