Synthesis of apicidin-derived quinolone derivatives: parasite-selective histone deacetylase inhibitors and antiproliferative agents.
Apicidin's indole was efficiently converted into a series of N-substituted quinolone derivatives by indole N-alkylation followed by a two-step, one-pot, ozonolysis/aldol condensation protocol. The new quinolones exhibited good parasite selectivity and potency both at the level of their molecular target, histone deacetylase, and in their whole cell antiproliferative activity in vitro.
Meinke
P T
PT
Merck Research Laboratories, P.O. Box 2000, RY800-B101, Rahway, New Jersey 07065-0900, USA. peter_meinke@merck.com
Colletti
S L
SL
Doss
G
G
Myers
R W
RW
Gurnett
A M
AM
Dulski
P M
PM
Darkin-Rattray
S J
SJ
Allocco
J J
JJ
Galuska
S
S
Schmatz
D M
DM
Wyvratt
M J
MJ
Fisher
M H
MH
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000981:Antiprotozoal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D002455:Cell Division / Q000187:drug effects; D002457:Cell Extracts; D002645:Chickens; D016786:Eimeria tenella / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D010456:Peptides, Cyclic / Q000737:chemistry*; D010963:Plasmodium falciparum / Q000187:drug effects; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000962:Antimalarials; D000981:Antiprotozoal Agents; D002457:Cell Extracts; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D007211:Indoles; D010456:Peptides, Cyclic; D015363:Quinolones; C102351:apicidin; D006655:Histone Deacetylases