title: Synthesis of betulinic acid derivatives as entry inhibitors against HIV-1 and bevirimat-resistant HIV-1 variants.
abstract: Betulinic acid derivatives modified at the C28 position are HIV-1entry inhibitors such as compound A43D; however, modified at the C3 position instead of C28 give HIV-1 maturation inhibitor such as bevirimat. Bevirimat exhibited promising pharmacokinetic profiles in clinical trials, but its effectiveness was compromised by the high baseline drug resistance of HIV-1 variants with polymorphism in the putative drug binding site. In an effort to determine whether the viruses with bevirimat resistant polymorphism also altered their sensitivities to the betulinic acid derivatives that inhibit HIV-1 entry, a series of new betulinic acid entry inhibitors were synthesized and tested for their activities against HIV-1 NL4-3 and NL4-3 variants resistant to bevirimat. The results show that the bevirimat resistant viruses were approximately 5- to10-fold more sensitive to three new glutamine ester derivatives (13, 15 and 38) and A43D in an HIV-1 multi-cycle replication assay. In contrast, the wild type NL4-3 and the bevirimat resistant variants were equally sensitive to the HIV-1 RT inhibitor AZT. In addition, these three new compounds markedly improved microsomal stability compared to A43D.
authors: Surgical Science, Department of Surgery, Box 2926, Duke University Medical Center, Durham, NC 27710-2926, USA.
authors: Zhao
authors: Z
authors: Dang
authors: Keduo
authors: K
authors: Qian
authors: Phong
authors: P
authors: Ho
authors: Lei
authors: L
authors: Zhu
authors: Kuo-Hsiung
authors: KH
authors: Lee
authors: Li
authors: L
authors: Huang
authors: Chin-Ho
authors: CH
authors: Chen
mesh_terms: D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D024882:Drug Resistance, Viral / Q000187:drug effects*; D005973:Glutamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D053978:Pentacyclic Triterpenes; D013329:Structure-Activity Relationship; D014315:Triterpenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D053586:Virus Internalization / Q000187:drug effects; D000094062:Betulinic Acid
chemical_list: D019380:Anti-HIV Agents; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; D005973:Glutamine; D000094062:Betulinic Acid