The complete stereochemistry of the antibiotic candicidin A3 (syn. ascosin A3, levorin A3)

Abstract

Herein, the stereostructure of the aromatic heptaene macrolide (AHM) antifungal antibiotic candicidin A3 (syn. ascosin A3, levorin A3) has been established upon the 2D NMR studies, consisting of DQF-COSY, TOCSY, ROESY, HSQC & HMBC experiments, as well as upon extensive molecular dynamics simulations. The geometry of the heptaenic chromophore was defined as: (22E, 24E, 26Z, 28Z, 30E, 32E, 34E). The previously unreported absolute configuration of the chiral centres of candicidin A3 was established as: (3R,

Ipertrofan Revisited—The Proposal of the Complete Stereochemistry of Mepartricin A and B

“…This procedure was previously successfully applied for the definition of stereochemistry of almost 20 polyene macrolides and their derivatives, including: the candicidins [ 17 , 18 , 19 , 20 ], rimocidin [ 21 ], candidin [ 22 ], mycoheptin A2 [ 23 ], etc. In this standardized approach, DQF-COSY and TOCSY experiments have allowed tracing of connectivities within isolated proton spin systems, separated by quaternary carbon atoms and oxygen-involving lactone and glycosidic bonds.…”

Iso-Partricin, an Aromatic Analogue of Amphotericin B: How Shining Light on Old Drugs Might Help Create New Ones

“…Detailed NMR studies revealed that, in contrary to the NMR data on the partricin A and partricin B methoxycarbonylmethylamide derivatives [8][9][10], all the 3 J H,H coupling constants within the double bonds were no lower than 15.1 Hz and no higher than 15.6 Hz, thus determining the E geometry of the entire chromophore systems. The chemical shifts of all the olefinic carbons (C22-C35) ranged between 130 and 137 ppm, which strongly suggested the E geometries of all the double bonds within the chromophores, since no shielding γ-effects were observed for the C27/C30 and C29/C32 pairs [9,16,22]. Moreover, rich sets of ROEs between the protons of the C2-C13 and C22-C35 fragments were recorded (Figure 3), as well as two uninterrupted ROE pathways, incorporating even-and odd-numbered olefinic protons (see Appendix A section, Table A1).…”

“…The native partricin complex was derivatized into its N-acetyl methyl ester via series of simple reactions. This procedure, developed at our department, is a well-established approach for the elucidation of constitution and/or stereochemistry of polyene macrolides, using NMR techniques [5,16,[20][21][22], and, as an option, could be followed in order to facilitate purification of studied antibiotic molecules and enhance their solubility in standard NMR solvents. Later, the resulting methyl ester of N-acetylpartricin (referred to as partricin*) was exposed to moderate UV-VIS radiation of λ = 365 nm.…”

“…Iso-partricin A* and iso-partricin B* molecules were subjects to a standard set of 2D NMR experiments, consisting of DQF-COSY, TOCSY, HSQC, HMBC and ROESY spectra (please consult Figures S1-S12) [5,16,[20][21][22][23][24][25][26]. DQF-COSY, TOCSY and HSQC spectra were used to trace proton-proton and proton-carbon connectivities within isolated protonic spin systems, while HMBC and ROESY experiments enabled gluing all the pieces together, due to long ranged heteronuclear couplings and structurally conclusive dipolar couplings between protons.…”

“…Derivatization of the purified partricin complex was performed with the general procedure previously elaborated in our laboratory and described in References [5,21,22].…”