Correlation of anti-HIV activity with anion spacing in a series of cosalane analogues with extended polycarboxylate pharmacophores.
Cosalane and its synthetic derivatives inhibit the binding of gp120 to CD4 as well as the fusion of the viral envelope with the cell membrane. The binding of the cosalanes to CD4 is proposed to involve ionic interactions of the negatively charged carboxylates of the ligands with positively charged arginine and lysine amino acid side chains of the protein. To investigate the effect of anion spacing on anti-HIV activity in the cosalane system, a series of cosalane tetracarboxylates was synthesized in which the two proximal and two distal carboxylates are separated by 6--12 atoms. Maximum activity was observed when the proximal and distal carboxylates are separated by 8 atoms. In a series of cosalane amino acid derivatives containing glutamic acid, glycine, aspartic acid, beta-alanine, leucine, and phenylalanine residues, maximum activity was displayed by the di(glutamic acid) analogue. A hypothetical model has been devised for the binding of the cosalane di(glutamic acid) conjugate to CD4. In general, the compounds in this series are more potent against HIV-1(RF) in CEM-SS cells than they are vs HIV-1(IIIB) in MT-4 cells, and they are least potent vs HIV-2(ROD) in MT-4 cells.
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907, USA.
K C
KC
Santhosh
G C
GC
Paul
E
E
De Clercq
C
C
Pannecouque
M
M
Witvrouw
T L
TL
Loftus
J A
JA
Turpin
R W
RW
Buckheit
M
M
Cushman
D000838:Anions / Q000737:chemistry; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001312:Aurintricarboxylic Acid / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015704:CD4 Antigens / Q000737:chemistry; D002460:Cell Line; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008958:Models, Molecular; D013329:Structure-Activity Relationship
D000838:Anions; D019380:Anti-HIV Agents; D015704:CD4 Antigens; C083060:cosalane; D001312:Aurintricarboxylic Acid