Synthesis and antiviral activity of 2-substituted analogs of triciribine.
Triciribine (TCN) and triciribine monophosphate (TCN-P) have antiviral and antineoplastic activity at low or submicromolar concentrations. In an effort to improve and better understand this activity, we have conducted a structure-activity relationship study to explore the effect of substitutions at the 2-position of triciribine. 2-Methyl- (2-Me-TCN), 2-ethyl- (2-Et-TCN), 2-phenyl- (2-Ph-TCN), 2-chloro- (2-Cl-TCN), and 2-aminotriciribine (2-NH2-TCN) were designed and synthesized to determine the effects of substitutions at the 2-position which change the steric, electronic, and hydrophobic properties of TCN, while maintaining the integrity of the tricyclic ring system. These compounds were evaluated for activity against human immunodeficiency virus (HIV-1), herpes simplex virus type 1 (HSV-1), and human cytomegalovirus (HCMV) and were found to be either less active than TCN and TCN-P or inactive at the highest concentrations tested, 100 microM. We conclude that substitutions at the 2-position of triciribine adversely affect the antiviral activity most likely because these analogs are not phosphorylated to active metabolites.
Porcari
Anthony R
AR
Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA. Anthony.Porcari@pfizer.com
Ptak
Roger G
RG
Borysko
Katherine Z
KZ
Breitenbach
Julie M
JM
Drach
John C
JC
Townsend
Leroy B
LB
D000073:Acenaphthenes; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003587:Cytomegalovirus / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects; D018259:Herpesvirus 1, Human / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D007624:KB Cells; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D011684:Purine Nucleosides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D012263:Ribonucleosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D012265:Ribonucleotides / Q000737:chemistry / Q000494:pharmacology
D000073:Acenaphthenes; D000998:Antiviral Agents; D011684:Purine Nucleosides; D012263:Ribonucleosides; D012265:Ribonucleotides; C023764:triciribine; C014205:triciribine phosphate