Abstract
Being a methyl ester of partricin, the mepartricin complex is the active substance of a drug called Ipertrofan (Tricandil), which was proven to be useful in treatment of benign prostatic hyperplasia and chronic nonbacterial prostatitis/chronic pelvic pain syndrome. Nevertheless, no direct structural evidence on the stereochemistry of its components has been presented to date. In this contribution, we have conducted detailed, NMR-driven stereochemical studies on mepartricins A and B, aided by molecular dynamics simulations. The absolute configuration of all the stereogenic centers of mepartricin A and B was defined as 3R, 7R, 9R, 11S, 13S, 15R, 17S, 18R, 19S, 21R, 36S, 37R, and 38S, and proposed as 41R. The geometry of the heptaenic chromophore of both compounds has been established as 22E, 24E, 26E, 28Z, 30Z, 32E, and 34E. Our studies on mepartricin ultimately proved that partricins A and B are structurally identical to the previously described main components of the aureofacin complex: gedamycin and vacidin, respectively. The knowledge of the stereochemistry of this drug is a fundamental matter not only in terms of studies on its molecular mode of action, but also for potential derivatization, aiming at improvement of its pharmacological properties.
Highlights
Mepartricin is a semi-synthetic polyene macrolide complex [1], consisting of two major components, namely mepartricin A and B
Mepartricin is the active substance of a drug called Ipertrofan (Tricandil), which was proven to be useful in treatment of benign prostatic hyperplasia (BPH) [2,3,4] and chronic nonbacterial prostatitis/chronic pelvic pain syndrome (CPPS) [5]
The above proposal of C41 s absolute configuration was strongly supported by the fact that all stereostructurally elucidated aromatic heptaene macrolides, containing alkyl-aromatic sidechain with hydroxylic moiety attached to C41, exhibited identical stereochemistry of this asymmetric center [17,20]
Summary
Mepartricin is a semi-synthetic polyene macrolide complex [1], consisting of two major components, namely mepartricin A and B. To all members of the heptaenic family of polyene macrolides, mepartricin effectively binds to steroids [9] This feature is being considered as the most probable molecular foundation of the therapeutic effect. TThheerreeffoorree,, hheerreeiinn wwee rreeppoorrtt NNMMRR--eevviiddeenncceedd aanndd mmoolleeccuullaarr--mmooddeelllliinngg--aaiiddeedd sstteerreeoo-cchheemmiissttrryy aassssiiggnnmmeenntt ooff IIppeerrttrrooffaann aaccttiivvee aaggeennttss:: mmeeppaarrttrriicciinnss AA aanndd BB——ii..ee..,, tthhee mmeetthhyyll eesstteerrss ooff ppaarrttrriicciinn AA aanndd BB,, rreessppeeccttiivveellyy ((FFiigguurree 11)). If a monosaccharide bound to a macrolactone ring—usually a D-aminosugar—produces dipolar couplings to the protons of the aglycone, these ROEs unambiguously define the absolute configuration of the aforementioned hydroxymethine carbon This observation, which was first reported during the model studies on amphotericin B [24], has laid a foundation for a general method of the elucidation of the absolute configuration of chiral secondary alcohols [25,26]
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