Novel analogs of D-e-MAPP and B13. Part 1: synthesis and evaluation as potential anticancer agents.
A series of novel isosteric analogs of the ceramidase inhibitors, (1S,2R)-N-myristoylamino-phenylpropanol-1 (d-e-MAPP) and (1R,2R)-N-myristoylamino-4'-nitro-phenylpropandiol-1,3 (B13), with modified targeting and physicochemical properties were designed, synthesized, and evaluated as potential anticancer agents. When MCF7 cells were treated with the analogs, results indicated that the new analogs were of equal or greater potency compared to the parent compounds. Their activity was predominantly defined by the nature of the modification of the N-acyl hydrophobic interfaces: N-acyl analogs (class A), urea analogs (class B), N-alkyl analogs (class C, lysosomotropic agents), and omega-cationic-N-acyl analogs (class D, mitochondriotropic agents). The most potent compounds belonged to either class D, the aromatic ceramidoids, or to class C, the aromatic N-alkylaminoalcohols. Representative analogs selected from this study were also evaluated by the National Cancer Institute In Vitro Anticancer Drug Discovery Screen. Again, results showed a similar class-dependent activity. In general, the active analogs were non-selectively broad spectrum and had promising activity against all cancer cell lines. However, some active analogs of the d-e-MAPP family were selective against different types of cancer. Compounds LCL85, LCL120, LCL385, LCL284, and LCL204 were identified to be promising lead compounds for therapeutic development.
Szulc
Zdzislaw M
ZM
Department of Biochemistry & Molecular Biology, Medical University of South Carolina, 173 Ashley Avenue, POB 250509, Charleston, SC 29425, USA.
Mayroo
Nalini
N
Bai
AiPing
A
Bielawski
Jacek
J
Liu
Xiang
X
Norris
James S
JS
Hannun
Yusuf A
YA
Bielawska
Alicja
A
D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000145:classification / Q000494:pharmacology*; D055572:Ceramidases; D020650:Combinatorial Chemistry Techniques; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D009226:Myristates / Q000138:chemical synthesis* / Q000737:chemistry / Q000145:classification / Q000494:pharmacology*; D011412:Propanolamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000145:classification / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C539749:2-N-(tetradecylamino)-1-phenyl-1,3-propanediol; D000577:Amides; D000970:Antineoplastic Agents; D009226:Myristates; C421619:N-(1-(4-nitrophenyl)-1,3-dihydroxyprop-2-yl)tetradecanamide; D011412:Propanolamines; C099657:2-(N-myristoylamino)-1-phenyl-1-propanol; D000581:Amidohydrolases; D055572:Ceramidases