The synthesis and evaluation of a solution phase indexed combinatorial library of non-natural polyenes for reversal of P-glycoprotein mediated multidrug resistance.
A combinatorial library of polyenes, based on (-)-stipiamide, has been constructed and evaluated for the discovery of new multidrug resistance reversal agents. A palladium coupling was used to react each individual vinyl iodide with a mixture of the seven acetylenes at near 1:1 stoichiometry. The coupling was also used to react each individual acetylene with the mixture of six vinyl iodides to create 13 pools indexed in two dimensions for a total of 42 compounds. Individual compounds were detected at equimolar concentration. The vinyl iodides, made initially using a crotylborane addition to generate the anti1,2-hydroxylmethyl products, were now made using a more efficient norephedrine propionate boron enolate aldol reaction. The indexed approach, ideally suited for cellular assays that involve membrane-bound targets, allowed for the rapid identification of reversal agents using assays with drug-resistant human breast cancer MCF7-adrR cells. Intersections of potent pools identified new compounds with promising activity. Aryl dimension pools showed R = ph and naphthyl as the most potent. The acetylene dimension had R' = phenylalaninol and alaninol as the most potent. Isolated individual compounds, both active and nonpotent, were assayed to confirm the library results. The most potent new compound was 4ek (R = naphthyl, R' = phenylaninol) at 1.45 microM. Other nonnatural individual naphthyl-amide compounds showed potent MDR reversal including the morpholino-amide 4ej (1.69 microM). Synergistic activities attributed to the two ends of the molecule were also identified. Direct interaction with Pgp was established by ATPase and photoaffinity displacement assays. The results indicate that both ends of the polyene reversal agent are involved in Pgp interaction and can be further modified for increased potency.
Andrus
M B
MB
Brigham Young University, Department of Chemistry and Biochemistry, C100 BNSN, Provo, Utah 84602-5700, USA. mbandrus@chemdept.byu.edu
Turner
T M
TM
Sauna
Z E
ZE
Ambudkar
S V
SV
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D020650:Combinatorial Chemistry Techniques; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D011090:Polyenes / Q000138:chemical synthesis* / Q000494:pharmacology; D011804:Quinolines / Q000032:analysis; D012996:Solutions; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D011090:Polyenes; D011804:Quinolines; D012996:Solutions; D004317:Doxorubicin; C047117:bicinchoninic acid; D000251:Adenosine Triphosphatases