Synthesis and discovery of water-soluble microtubule targeting agents that bind to the colchicine site on tubulin and circumvent Pgp mediated resistance.
Two classes of molecules were designed and synthesized based on a 6-CH(3) cyclopenta[d]pyrimidine scaffold and a pyrrolo[2,3-d]pyrimidine scaffold. The pyrrolo[2,3-d]pyrimidines were synthesized by reacting ethyl 2-cyano-4,4-diethoxybutanoate and acetamidine, which in turn was chlorinated and reacted with the appropriate anilines to afford 1 and 2. The cyclopenta[d]pyrimidines were obtained from 3-methyladapic acid, followed by reaction with acetamidine to afford the cyclopenta[d]pyrimidine scaffold. Chlorination and reaction with appropriate anilines afforded (±)-3·HCl-(±)-7·HCl. Compounds 1 and (±)-3·HCl had potent antiproliferative activities in the nanomolar range. Compound (±)-3·HCl is significantly more potent than 1. Mechanistic studies showed that 1 and (±)-3·HCl cause loss of cellular microtubules, inhibit the polymerization of purified tubulin, and inhibit colchicine binding. Modeling studies show interactions of these compounds within the colchicine site. The identification of these new inhibitors that can also overcome clinically relevant mechanisms of drug resistance provides new scaffolds for colchicine site agents.
Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, Pennsylvania 15282, USA. gangjee@duq.edu
Aleem
A
Gangjee
Ying
Y
Zhao
Lu
L
Lin
Sudhir
S
Raghavan
Elizabeth G
EG
Roberts
April L
AL
Risinger
Ernest
E
Hamel
Susan L
SL
Mooberry
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D000818:Animals; D001665:Binding Sites; D002417:Cattle; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003078:Colchicine / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism*; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014867:Water
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; C554512:N-(4-methoxyphenyl)-N,2,6-trimethyl-6,7-dihydro-5H-cyclopenta(d)pyrimidin-4-amine; C554511:N-(4-methoxyphenyl)-N,2-dimethyl-7H-pyrrolo(2,3-d)pyrimidin-4-amine; D011743:Pyrimidines; D011758:Pyrroles; D014404:Tubulin; D050257:Tubulin Modulators; D014867:Water; D003078:Colchicine