Novel analogs of D-e-MAPP and B13. Part 2: signature effects on bioactive sphingolipids.
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 developed and evaluated for their effects on endogenous bioactive sphingolipids: ceramide, sphingosine, and sphingosine 1-phosphate (Cer, Sph, and S1P) in MCF7 cells as determined by high-performance liquid chromatography-mass spectrometry (HPLC-MS/MS). Time- and dose-response studies on the effects of these compounds on Cer species and Sph levels, combined with structure-activity relationship (SAR) data, revealed 4 distinct classes of analogs which were predominantly defined by modifications of the N-acyl-hydrophobic interfaces: N-acyl-analogs (class A), urea-analogs (class B), N-alkyl-analogs (class C), and omega-cationic-N-acyl analogs (class D). Signature patterns recognized for two of the classes correspond to the cellular compartment of action of the new analogs, with class D acting as mitochondriotropic agents and class C compounds acting as lysosomotropic agents. The neutral agents, classes A and B, do not have this compartmental preference. Moreover, we observed a close correlation between the selective increase of C(16)-, C(14)-, and C(18)-Cers and inhibitory effects on MCF7 cell growth. The results are discussed in the context of compartmentally targeted regulators of Sph, Cer species, and S1P in cancer cell death, emphasizing the role of C(16)-Cer. These novel analogs should be useful in cell-based studies as specific regulators of Cer-Sph-S1P inter-metabolism, in vitro enzymatic studies, and for therapeutic development.
Bielawska
Alicja
A
Department of Biochemistry & Molecular Biology, Medical University of South Carolina, 173 Ashley Avenue, PO Box 250509, Charleston, SC 29425, USA. bielawsk@musc.edu
Bielawski
Jacek
J
Szulc
Zdzislaw M
ZM
Mayroo
Nalini
N
Liu
Xiang
X
Bai
AiPing
A
Elojeimy
Saeed
S
Rembiesa
Barbara
B
Pierce
Jason
J
Norris
James S
JS
Hannun
Yusuf A
YA
D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000145:classification / 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*; D013107:Sphingolipids / Q000378:metabolism*; D013237:Stereoisomerism
D000577:Amides; D000970:Antineoplastic Agents; D009226:Myristates; C421619:N-(1-(4-nitrophenyl)-1,3-dihydroxyprop-2-yl)tetradecanamide; D011412:Propanolamines; D013107:Sphingolipids; C099657:2-(N-myristoylamino)-1-phenyl-1-propanol; D000581:Amidohydrolases; D055572:Ceramidases