Synthesis, Src kinase inhibitory and anticancer activities of 1-substituted 3-(N-alkyl-N-phenylamino)propane-2-ols.
A series of 3-(N-alkyl-N-phenylamino)propan-2-ol derivatives were synthesized from epichlorohydrine in a multi-step strategy and were evaluated as Src kinase inhibitors. First, epoxy ring opening of epichlorohydrine was carried out in the presence of N-alkylanilines to yield 3-(N-alkyl-N-phenylamino)-1-chloro-propan-2-ol derivatives using Ca(OTf)2 as catalyst based on our previous studies [1]. Second, ring closure was performed under basic conditions to afford N-epoxymethyl N-alkylaniline derivatives. Finally, the epoxide ring opening with four different secondary amines and three nucleobases afforded the final products, i.e., a series of beta-amino alcohols. All compounds were screened for their inhibitory activity against Src kinase and anticancer activity on human breast carcinoma cells, BT-20 cell line. Among all compounds, 3-N-methyl-N-phenylamino-1-(pyrrolidin-1-yl)propan-2-ol (13b) exhibited the highest inhibitory potency (IC50=66.1 microM) against Src kinase. Structure-activity relationship studies suggested that the incorporation of bulky groups at position 1 and N-substitution with groups larger than methyl moiety, reduced the inhibitory potency of the compound significantly. Compounds 3-(N-ethyl-N-phenylamino-)-1-(4-methylpiperazin-1-yl)propan-2-ol (14c) and 3-(N-ethyl-N-phenylamino)-1-(thymine-1-yl)propan-2-ol (17) were found to inhibit the growth of breast carcinoma cells by approximately 45-49% at concentration of 50 microM.
Sharma
Deepti
D
Bioorganic Laboratory, Department of Chemistry, University of Delhi, Delhi 110 007, India.
Sharma
Raman K
RK
Bhatia
Sumati
S
Tiwari
Rakesh
R
Mandal
Deendayal
D
Lehmann
Jessica
J
Parang
Keykavous
K
Olsen
Carl E
CE
Parmar
Virinder S
VS
Prasad
Ashok K
AK
D000605:Amino Alcohols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
D000605:Amino Alcohols; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D019061:src-Family Kinases