Synthesis and biological evaluation of dihydromotuporamine derivatives in cells containing active polyamine transporters.
Dihydromotuporamine C (4) and its 4,4-triamine analogue (5) were synthesized in good yield using ring-closing metathesis (RCM) methods. Comparison of their biological activities (Ki determinations in L1210 cells and IC50 determinations in L1210, CHO, and CHO-MG cells) revealed that the motuporamine derivatives do not use the polyamine transporter (PAT) for cellular entry. Bioevaluation of a N1-(anthracen-9-ylmethyl)-N1-(ethyl)homospermidine control (7) revealed that the presence of a N1 tertiary amine center imparted a significant reduction in the PAT affinity of the polyamine conjugate and abolished its PAT-targeting selectivity.
Kaur
Navneet
N
Department of Chemistry, University of Central Florida, P.O. Box 162366, Orlando, Florida 32816-2366, USA.
Delcros
Jean-Guy
JG
Martin
Bénédicte
B
Phanstiel
Otto
O
D000818:Animals; D000873:Anthracenes / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D016466:CHO Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D051379:Mice; D009154:Mutation; D011073:Polyamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D013095:Spermidine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
D000873:Anthracenes; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D011073:Polyamines; D013095:Spermidine