Indolocarbazoles: potent, selective inhibitors of human cytomegalovirus replication.
In our search for new, safer anti-HCMV agents, we discovered that the natural product Arcyriaflavin A (la) was a potent inhibitor of HCMV replication in cell culture. A series of analogues (symmetrical indolocarbazoles) was synthesised to investigate structure activity relationships in this series against a range of herpes viruses (HCMV, VZV, HSV1, and 2). This identified a number of novel, selective and potent inhibitors of HCMV, 12,13-dihydro-2,10-difluoro-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazol e-5,7-(6H)-dione (1d) being the best example (IC50=40 nM, therapeutic index > 1450). Compounds described in this series were generally poor inhibitors of protein kinase C betaII, and no correlation was found between the ability to inhibit HCMV and the enzyme PKC.
Slater
M J
MJ
GlaxoWellcome Medicines Research Centre, Stevenage, UK. MJS40312@glaxowellcome.co.uk
Cockerill
S
S
Baxter
R
R
Bonser
R W
RW
Gohil
K
K
Gowrie
C
C
Robinson
J E
JE
Littler
E
E
Parry
N
N
Randall
R
R
Snowden
W
W
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002227:Carbazoles / Q000737:chemistry / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002522:Chlorocebus aethiops; D003587:Cytomegalovirus / Q000187:drug effects* / Q000502:physiology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D006564:Herpesviridae / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D051381:Rats; D013329:Structure-Activity Relationship; D014709:Vero Cells; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D002227:Carbazoles; D004791:Enzyme Inhibitors; C089657:arcyriaflavin A; D011493:Protein Kinase C