Evodiamine and rutaecarpine alkaloids as highly selective transient receptor potential vanilloid 1 agonists.
Despite that among non-camptothecin natural products promising anticancer therapeutics are evodiamine derivatives, involved into mechanism of physiological function of topoisomerase-I. But, more recent findings have been shown that substituted quinazole alkaloids act as transient receptor potential vanilloid 1 agonists. The TRP(V1) is a calcium ion channel, activated by pH, heat and inflammatory activators. I is implicated in pain sensing. TRPV1 agonist is capsaicine (1). Both 1 and evodiamine (2), therefore, produce same physiological response, but are structurally unrelated from chemical viewpoint. Furthermore precise mechanistic aspects of drugs receptor interactions are still not fully understood. This study is the first one, which provides assessment of molecular factors contributing significantly to selectivity of 2 and rutaecarpine (3) as well as their twenty-two new functionalized derivatives towards (TRP)V1. The suggested new functionalization type of molecular skeleton, which is completely different one in respect the known derivatives, which is implicated in treatment of variety of cancer cell lines interacting preferably with topoisomerase-I. It resulted to increasing of the binding affinity and selectivity of the functionalized derivatives specifically to (TRP)V1∈1.36-1.72 and ∈2.50-3.16 higher than 1-3.
Lehrstuhl für Analytische Chemie, Institut für Umweltforschung, Fakultät für Chemie und Chemische Biologie, Universität Dortmund, Otto-Hahn-Straße 6, 44221 Dortmund, Nordrhein-Westfalen, Germany. Electronic address: B.Ivanova@web.de.
Bojidarka
B
Ivanova
Lehrstuhl für Analytische Chemie, Institut für Umweltforschung, Fakultät für Chemie und Chemische Biologie, Universität Dortmund, Otto-Hahn-Straße 6, 44221 Dortmund, Nordrhein-Westfalen, Germany.
Michael
M
Spiteller
D000818:Animals; D006801:Humans; D026121:Indole Alkaloids / Q000378:metabolism / Q000494:pharmacology*; D008958:Models, Molecular; D011487:Protein Conformation; D011799:Quinazolines / Q000378:metabolism / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D013379:Substrate Specificity; D050916:TRPV Cation Channels / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D052999:Quinazolinones
D026121:Indole Alkaloids; D011799:Quinazolines; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; C028632:rutecarpine; D052999:Quinazolinones; C049639:evodiamine
(TRP)V1 agonists; Drugs-design; Evodiamine type alkaloids; Mass spectrometry; Quantum chemistry