Chemistry of Renieramycins. 17. A New Generation of Renieramycins: Hydroquinone 5-O-Monoester Analogues of Renieramycin M as Potential Cytotoxic Agents against Non-Small-Cell Lung Cancer Cells

Abstract

A series of hydroquinone 5-O-monoester analogues of renieramycin M were semisynthesized via bishydroquinonerenieramycin M (5) prepared from renieramycin M (1), a major cytotoxic bistetrahydroisoquinolinequinone alkaloid isolated from the Thai blue sponge Xestospongia sp. All 20 hydroquinone 5-O-monoester analogues possessed cytotoxicity with IC values in nanomolar concentrations against the H292 and H460 human non-small-cell lung cancer (NSCLC) cell lines. The improved cytotoxicity toward the NSCLC cell lines was observed from the 5-O-monoester analogues such as 5-O-acetyl ester 6a and 5-O-propanoyl ester 7e, which exhibited 8- and 10-fold increased cytotoxicity toward the H292 NSCLC cell line (IC 3.0 and 2.3 nM, respectively), relative to 1 (IC 24 nM). Thus, the hydroquinone 5-O-monoester analogues are a new generation of the renieramycins to be further developed as potential marine-derived drug candidates for lung cancer treatment.

Structure–Activity Relationships and Molecular Docking Analysis of Mcl-1 Targeting Renieramycin T Analogues in Patient-derived Lung Cancer Cells

“…by pretreatment with potassium cyanide in a study in 2009 [45]. Recently, its anti-cancer activities have been reported against several types of cancer cells, such as colon (HCT116), prostate (DU145) [46], non-small cell lung (H292, H460, and QG56) [47], breast (T47D), and pancreatic (AsPC1) cancer cells [45]. Moreover, a modified form of RT, 5-O-acetyl-renieramycin T, was shown to induce the death of lung cancer stem cells and sensitize cisplatin-mediated apoptosis in lung cancer cells [48].…”

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

“…The preparation of 22- O -amino ester derivatives of 1 involved the transformation of 1 to jorunnamycin A ( 7 ) by the well-known three-step procedure including hydrogenation, hydride reduction, and air oxidation [ 16 , 27 ]. Next, 7 was reacted with the commercially available N - tert -butyloxycarbonyl (Boc)-protected amino acids including N -Boc- l -glycine, N -Boc- l -alanine, N -Boc- l -phenylalanine, N -Boc- l -valine, and N -Boc- l -proline under the Steglich esterification in the presence of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI) as a coupling reagent to furnish the desired 22- O -amino ester derivatives of 1 in moderate to excellent yields ( Scheme 1 ) [ 18 ].…”

“…The Steglich esterification was employed for the regiospecific esterification at the hydroxyl group on C-5, which was located at the least steric hindrance position. After esterification, the hydroquinone at ring E was restored by air oxidation to give back the quinone moiety, yielding the hydroquinone 5- O amino ester derivatives ( 6 ) [ 15 , 18 ]. Although the Steglich esterification with EDCI and N , N -4-dimethylaminopyridine (DMAP) was selected based on its mild and highly effective condition [ 28 ], the hydroquinone 5- O -amino ester derivatives were obtained at low to moderate yields due to the steric hindrances surrounding the hydroxyl group at C-5 of 8 and the N -Boc- l -amino acid.…”

“…Interestingly, 1 and its semi-synthetic derivatives, replacing the angelate ester at various new ester side chains at C-22, exhibited a moderate to high potency of cytotoxicity in the nanomolar range against several human cancer cell lines such as colon, lung, and breast carcinomas [ 16 ]. In the past several years, the prominent structure–activity relationship studies of 1 and its semi-synthetic derivatives featuring various linear and aromatic ester side chains at C-22 and C-5 have been continuously explored and evaluated for their cytotoxic activity against non-small-cell lung cancer cell lines [ 17 , 18 ], which have been listed as one of the world’s leading causes of death [ 19 , 20 ]. Based on the current findings, the chemically modified ester side chains at C-22 and C-5 displayed a key structure-cytotoxicity relationship.…”

Novel platinum agents and mesenchymal stromal cells for thoracic malignancies: state of the art and future perspectives

“…17 Valid alternative anticancer alkaloids resulted the marine-derived molecules capable to interact with different targets. A series of analogues of renieramycin M(Figure 1, series III)possessed a nanomolar concentration cytotoxic activity against H292 and H490 human NSCLC cell lines.Investigation about the mechanism of action is in progress, allowing a future clinical application of the molecules considering the high activity demonstrated on lung cancer 18.…”