Photochemical reaction of renieramycins and evaluation of cytotoxicity against lung cancer cells

Abstract

Lung cancer causes more deaths than any other type of cancers, with the majority of patients diagnosed with non-small cell lung cancer (NSCLC). Lung cancer is a difficult disease to treat because of the drug resistant problem. Therefore, there is an immediate need for effective, safe, and easily accessible anti-lung cancer drug. Ecteinascidin 743 (Trabectedin or Yondelis®), a marine-derived tetrahydroisoquinoline alkaloid, is an approved drug for treating human lung cancer. This research was studied on the semi-syntheses of new renieramycins derivatives with similar structures to above drug for discovery and development of potent NSCLC cytotoxic agents. Renieramycins was extracted from Xestospongia sp., a blue sponge found at the vicinity of Si-Chang island, Chonburi, Thailand. Renieramycin M was reported as a major alkaloid possessing a bis-tetrahydroisoquinolinequinone as core structure. Regarding the previous report, renieramycin M shows cytotoxicity against NSCLC. Thus, structural modifications focusing on the transformation of substituents at carbon positions 7 and 8 of natural renieramycins including renieramycin M, N, and O were performed by photochemical reaction in conjugation with the reaction optimizations using various light sources and solvents to obtain the [1,3]-dioxole group at carbon positions 7 and 8, efficiently. The result showed that the photochemical reaction with blue light in dichloromethane furnished the highest yield. Under this optimized photochemical reaction, renieramycin M transformed to renieramycin T and renieramycin N and O produced renieramycin U. The results of photochemical reaction support chemical transformations of natural renieramycins under the ocean with sunlight exposure. Furthermore, semi-syntheses of the ester derivatives of renieranycins containing a 4'-pyridinecarbonyl substituent at carbon position 22, using an esterification reaction and new derivatives from the sequential esterification and photochemical reaction containing both 4'-pyridinecarbonyl substituent at carbon position 22 and [1,3]-dioxole group at carbon positions 7 and 8 were conducted. The series of natural renieramycins and derivatives totally 10 compounds were evaluated their cytotoxicity against H292 and H460 NSCLC cell lines. As the results, 22-O-(4'-pyridinecarbonyl) jorunnamycin A exhibited IC50 at 3.52 ± 0.62 µM and 3.98 ± 0.38 µM against H292 and H460, respectively with 10 and 8 folds more potent than that of renieramycin M, mother compound. Besides, 22-O-(4'-pyridinecarbonyl) renieramycin T showed IC50 at 1.27 ± 0.20 µM and 1.83 ± 0.83 µM against H292 and H460, respectively with 2 and 3 folds more potent than that of Cisplatin, a first-line chemotherapeutic drug. Hence, these new renieramycins derivatives are the promising candidates for further development an anti-lung cancer agent.