Chemistry of Renieramycins. Part 19: Semi-Syntheses of 22-O-Amino Ester and Hydroquinone 5-O-Amino Ester Derivatives of Renieramycin M and Their Cytotoxicity against Non-Small-Cell Lung Cancer Cell Lines

Abstract

Two new series of synthetic renieramycins including 22-O-amino ester and hydroquinone 5-O-amino ester derivatives of renieramycin M were semi-synthesized and evaluated for their cytotoxicity against the metastatic non-small-cell lung cancer H292 and H460 cell lines. Interestingly, the series of 22-O-amino ester derivatives displayed a potent cytotoxic activity greater than the hydroquinone derivatives. The most cytotoxic derivative of the series was the 22-O-(N-Boc-l-glycine) ester of renieramycin M (5a: IC50 3.56 nM), which showed 7-fold higher potency than renieramycin M (IC50 24.56 nM) and 61-fold more than jorunnamycin A (IC50 217.43 nM) against H292 cells. In addition, 5a exhibited a significantly higher cytotoxic activity than doxorubicin (ca. 100 times). The new semi-synthetic renieramycin derivatives will be further studied and developed as potential cytotoxic agents for non-small-cell lung cancer treatment.

22-O-(N-Boc-l-glycine) ester of renieramycin M inhibits migratory activity and suppresses epithelial–mesenchymal transition in human lung cancer cells

“…including renieramycin M and jorunnamycin A was highlighted through reports indicating suppression on anchorage-independent growth and sensitization of detachment-induced cell death in human lung cancer cells [31]. To maintain cytotoxicity and improve cancer selectivity, a semi-synthesized version of renieramycin M containing a hydroquinone amino ester extension was prepared to gain insights into anticancer activity and specific protein targets [34]. Taken together with the attenuation on migration and invasion activity presented in this study, the semi-synthesized hydroquinone monoester derivative of renieramycin M, 22-Boc-Gly-RM, has demonstrated multitargeted potential use against metastasis in human lung cancer cells.…”

“…22-O-(N-Boc-l-glycine) ester of renieramycin M (22-Boc-Gly-RM) was semi-synthesized from jorunnamycin A by esterification as described in the previous studies [34,37] (see Online Resource 1). The obtained yellow powder of 22-Boc-Gly-RM was kept at room temperature away from light and moisture until use.…”

“…In addition, anticancer activity of renieramycin T was evidenced with apoptosis-inducing effect [33]. Recently, the new series of hydroquinone monoester derivatives of renieramycin M have been reported as the potential cytotoxic agents against human lung cancer cells [34,35]. The hydroquinone analogues of renieramycin M such as hydroquinone 5-O-acetyl ester (4) and hydroquinone 5-O-cinnamoyl ester (5) significantly induced apoptosis by increasing expression of apoptosis-inducing factor [35,36].…”

“…The hydroquinone analogues of renieramycin M such as hydroquinone 5-O-acetyl ester (4) and hydroquinone 5-O-cinnamoyl ester (5) significantly induced apoptosis by increasing expression of apoptosis-inducing factor [35,36]. Among various semi-synthetic derivatives, 22-O-amino ester derivative of renieramycin M, namely 22-O-(N-Boc-l-glycine) ester of renieramycin M (6), exhibits potent anticancer activity against human lung cancer, which was indicated with lower half-maximal inhibitory concentration (IC 50 ) compared to renieramycin M [34]. However, the underlying mechanisms relating to migration and invasion of these marine alkaloids are not thoroughly elucidated.…”

Jorunnamycin A Suppresses Stem-Like Phenotypes and Sensitizes Cisplatin-Induced Apoptosis in Cancer Stem-Like Cell-Enriched Spheroids of Human Lung Cancer Cells

“…This natural marine product is similar to ecteinascidin 743 [ 30 ] and to renieramycin M, with the key difference being the side chain at the C-22 position ( Figure 1 ), as renieramycin M possesses an angeloyl ester while jorunnamycin A has an alcohol side chain instead. Jorunnamycin A and renieramycin M derivatives have exhibited potent cytotoxicity against human lung cancer cells [ 31 , 32 , 33 ]. A recent study revealed the inhibitory effect of renieramycin M on CSC features of lung cancer cells; however, its regulatory mechanism has never been investigated [ 34 ].…”