3-(4-Aroyl-1-methyl-1H-pyrrol-2-yl)-N-hydroxy-2-propenamides as a new class of synthetic histone deacetylase inhibitors. 3. Discovery of novel lead compounds through structure-based drug design and docking studies.
Aroyl-pyrrole-hydroxy-amides (APHAs) are a new class of synthetic HDAC inhibitors recently described by us. Through three different docking procedures we designed, synthesized, and tested two new isomers of APHA lead compound 3-(4-benzoyl-1-methyl-1H-pyrrol-2-yl)-N-hydroxy-2-propenamide (1), compounds 3 and 4, characterized by different insertions of benzoyl and propenoylhydroxamate groups onto the pyrrole ring. Biological activities of 3 and 4 were predicted by computational tools up to 617-fold more potent than that of 1 against HDAC1; thus, 3 and 4 were synthesized and tested against both mouse HDAC1 and maize HD2 enzymes. Predictions of biological affinities (K(i) values) of 3 and 4, performed by a VALIDATE model (applied on either SAD or automatic DOCK or Autodock results) and by the Autodock internal scoring function, were in good agreement with experimental activities. Ligand/receptor positive interactions made by 3 and 4 into the catalytic pocket, in addition to those showed by 1, could at least in part account for their higher HDAC1 inhibitory activities. In particular, in mouse HDAC1 inhibitory assay 3 and 4 were 19- and 6-times more potent than 1, respectively, and 3 and 4 antimaize HD2 activities were 16- and 76-times higher than that of 1, 4 being as potent as SAHA in this assay. Compound 4, tested as antiproliferative and cytodifferentiating agent on MEL cells, showed dose-dependent growth inhibition and hemoglobin accumulation effects.
Ragno
Rino
R
Dipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente Attive, Università degli Studi di Roma "La Sapienza", P. le A. Moro 5, 00185 Roma, Italy. antonello.mai@uniroma1.it
Mai
Antonello
A
Massa
Silvio
S
Cerbara
Ilaria
I
Valente
Sergio
S
Bottoni
Patrizia
P
Scatena
Roberto
R
Jesacher
Florian
F
Loidl
Peter
P
Brosch
Gerald
G
D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D015195:Drug Design; D006454:Hemoglobins / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000737:chemistry; D051379:Mice; D008958:Models, Molecular; D011422:Propionates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D003313:Zea mays
D000577:Amides; D000970:Antineoplastic Agents; D006454:Hemoglobins; D056572:Histone Deacetylase Inhibitors; D011422:Propionates; D011758:Pyrroles; D006655:Histone Deacetylases