Synthesis and Biological Evaluation of Macrocyclized Betulin Derivatives as a Novel Class of Anti-HIV-1 Maturation Inhibitors.

Jun Tang,Cristin M Galardi,Yajun Yu,Yufei Sun,Stacey A Jones,Nianhe Han,Rui Li,Daxin Gao,Chunyu Liu,Erjuan Wang,Brian A Johns,David M Irlbeck,Jerry L Jeffery,Caiming Xi,Bin Shen,Zhi‐Min Jin ,He-Ping Yang ,Sónia Miranda ,Kevin Brown ,Charlene Mcdanal ,Yuanzhao Wu

doi:10.2174/1874104501408010023

Abstract

A macrocycle provides diverse functionality and stereochemical complexity in a conformationally preorganized ring structure, and it occupies a unique chemical space in drug discovery. However, the synthetic challenge to access this structural class is high and hinders the exploration of macrocycles. In this study, efficient synthetic routes to macrocyclized betulin derivatives have been established. The macrocycle containing compounds showed equal potency compared to bevirimat in multiple HIV-1 antiviral assays. The synthesis and biological evaluation of this novel series of HIV-1 maturation inhibitors will be discussed.

Highlights

Long-term suppression of viral replication with antiretroviral drugs is the only option for treating HIV-1 infection
Therapeutic regimens known as highly active antiretroviral therapy (HAART) are often complex because a combination of different drugs must be administered to patients to avoid the rapid emergence of drugresistant HIV-1 variants
It was reported that bevirimat reduced HIV-1 viral load by a mean of 1.3-log copies/mL in patients who achieved through drug concentrations of 20 g/mL and did not have any of the key baseline Gag polymorphisms at positions Q369, V370 or T371

Summary

INTRODUCTION

Long-term suppression of viral replication with antiretroviral drugs is the only option for treating HIV-1 infection. Drug toxicity, adverse drug–drug interactions, and poor patient compliance can lead to treatment failure These will require continuous development of improved antiviral drugs with new targets and mechanisms of action [1]. Bevirimat (PA-457, MPC-4326) is a maturation inhibitor that inhibits the final step in the processing of Gag (Fig. 1). It showed activity against ART-resistant and wild-type HIV-1, and demonstrated synergy with antiretroviral agents from all other classes. It was reported that bevirimat reduced HIV-1 viral load by a mean of 1.3-log copies/mL in patients who achieved through drug concentrations of 20 g/mL and did not have any of the key baseline Gag polymorphisms at positions Q369, V370 or T371. The synthetic challenge to access this structural class is high and hinders the exploration of macrocycles for drug discovery

CHEMISTRY

BIOLOGICAL ACTIVITY OF THE DERIVATIVES

CONCLUSION