Non-peptide macrocyclic histone deacetylase inhibitors derived from tricyclic ketolide skeleton.
Inhibition of histone deacetylase (HDAC) function is a validated therapeutic strategy for cancer treatment. Of the several structurally distinct small molecule histone deacetylase inhibitors (HDACi) reported, macrocyclic depsipeptides possess the most complex cap groups and have demonstrated excellent HDAC inhibition potency and isoform selectivity. Unfortunately, the development of macrocyclic depsipeptides has been hampered in part because of development problems characteristic of large peptides and the complex reaction schemes required for their synthesis. Herein we report that tricyclic ketolide TE-802 is an excellent mimetic for the peptide backbone of macrocyclic HDACi. Compounds derived from this template are particularly selective against HDACs 1 and 2 with nanomolar inhibitory activity. Interrogation of the association between a subset of these compounds and key HDAC isoforms, using AutoDock, enables a molecular description of the interaction between the HDAC enzyme's outer rim and the inhibitors' macrocyclic cap group that are responsible for compound affinity and presumably isoform selectivity.
Mwakwari
Sandra C
SC
School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332-0400, USA.
Guerrant
William
W
Patil
Vishal
V
Khan
Shabana I
SI
Tekwani
Babu L
BL
Gurard-Levin
Zachary A
ZA
Mrksich
Milan
M
Oyelere
Adegboyega K
AK
D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D048628:Ketolides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007893:Leishmania donovani / Q000187:drug effects; D008958:Models, Molecular; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D000962:Antimalarials; D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D007527:Isoenzymes; D048628:Ketolides; D014344:Trypanocidal Agents