J Inorg Biochem. 2026 Jul 24;284:113417. doi: 10.1016/j.jinorgbio.2026.113417. Online ahead of print.
ABSTRACT
Chiral coordination complexes continue to attract interest as potential therapeutic agents, yet their stereochemical properties are rarely examined with the rigor now standard in organic drug discovery. Here we investigate whether the Δ and Λ enantiomers of the highly potent Ru(II) oligothienyl photosensitizer ML19G01 exhibit intrinsic differences in photobiological activity. Five independently synthesized batches of rac-ML19G01 were separated by direct chiral chromatography on a functionalized cyclofructan-6 (CF6-RN) stationary phase using both LC and sub/supercritical fluid chromatography. Enantiomeric excess was established by analytical chiral HPLC, absolute configuration was assigned by vibrational circular dichroism (VCD)/DFT comparison, and removal of trifluoroacetic acid (TFA), triethylamine (TEA), and counterion impurities was verified by 1H and 19F NMR. Enantiomeric integrity under illumination was confirmed to exclude photoracemization. Across 24 independent photobiological assays performed over several years in SK-MEL-28 melanoma cells, Δ- and Λ-ML19G01 displayed statistically indistinguishable dark and light EC50 values and phototherapeutic indices. Although individual experiments occasionally suggested enhanced potency of one enantiomer, these differences were not reproducible and were not supported by ANOVA/Tukey analysis. Small deviations observed for the racemate arose from non-stereochemical factors, including polymorphism, differential purification histories, and statistical averaging. These results demonstrate that ML19G01 does not exhibit meaningful enantiospecific photobiological behavior and provide practical recommendations for the preparation, characterization, and biological evaluation of chiral coordination complexes.
PMID:42531660 | DOI:10.1016/j.jinorgbio.2026.113417
