MDR Reversal by Deprenylated Tetracyclic and Hexacyclic Analogues of N-Acetylardeemin: Confirmation of the Ardeemin Pharmacophore

Avendaño, Carmen; Caballero, Esmeralda; Méndez-Vidal, Cristina; Quesada, Ana R.; Menéndez, J. Carlos

doi:10.2174/157018006777805558

Cited by 8 publications

(1 citation statement)

References 13 publications

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“…Marine alkaloids containing indolymethyl pyrazinoquinazoline ring system can be considered conformationally constrained peptidomimetics exhibiting very interesting biological properties [ 15 ]. For instance, glyantrypine ( 2 ) is an antibacterial agent, active against Vibrio harveyi [ 16 ]; fumiquinazolines are antitumor compounds with moderate cytotoxicity [ 17 ]; fiscalins are substance P inhibitors and anticancer agents [ 7 , 18 ]; cladoquinazolines ( 9 and 10 ) are active against influenza A virus (H 1 N 1 ); fumiquinazoline S ( 12 ) exhibits a weak inhibition against Na + /K + -ATPase, and N -acetylardeemin ( 14 ) is a potent inhibitor of multidrug resistant (MDR) tumor cells [ 4 , 13 , 19 , 20 ]. Moreover, the pyrazino[2,1- b ]quinazoline ring system has been already ascribed as essential for the above-mentioned activities, and its enantioselective effects were observed for their antibacterial activity.…”

Section: Introductionmentioning

confidence: 99%

Antitumor Activity of Quinazolinone Alkaloids Inspired by Marine Natural Products

et al. 2018

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Many fungal quinazolinone metabolites, which contain the methyl-indole pyrazino [1,2-b]quinazoline-3,6-dione core, have been found to possess promising antitumor activity. The purpose of this work was to synthesize the enantiomeric pairs of two members of this quinazolinone family, to explore their potential as antitumor and their ability to revert multidrug resistance. The marine natural product fiscalin B (4c), and antienantiomers (4b, 5b, and 5c) were synthesized via a one-pot approach, while the syn enantiomers (4a, 4d, 5a, and 5d) were synthetized by a multi-step procedure. These strategies used anthranilic acid (i), chiral N-protected α-amino acids (ii), and tryptophan methyl esters (iii) to form the core ring of pyrazino[2,1-b]quinazoline-3,6-dione scaffold. Four enantiomeric pairs, with different enantiomeric purities, were obtained with overall yields ranging from 7 to 40%. Compounds 4a–d and 5a–d were evaluated for their growth inhibitory effect against two tumor cell lines. Differences between enantiomeric pairs were noted and 5a–d displayed GI50 values ranging from 31 to 52 μM, which are lower than those of 4a–d. Nevertheless, no effect on P-glycoprotein (P-gp) modulation was observed for all compounds. This study disclosed new data for fiscalin B (4c), as well as for its analogues for a future development of novel anticancer drug leads.

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Section: Introductionmentioning

confidence: 99%

Antitumor Activity of Quinazolinone Alkaloids Inspired by Marine Natural Products

et al. 2018

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Reversal of multidrug resistance in vitro and in vivo by 5-N-formylardeemin, a new ardeemin derivative

Zheng

Zhao

et al. 2014

Apoptosis

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Because multidrug resistance (MDR) is a serious impediment to the use of chemotherapy in treating cancer patients, great efforts have been made to search for effective MDR-reversing agents. We have developed a brand new synthetic ardeemin derivative, 5-N-formylardeemin, and investigated the activity of which in reversing MDR in MDR cancer cell lines derived from human breast cancer (MCF-7-R) or lung cancer (A549-R). 5-N-formylardeemin strongly enhanced the anti-cancer efficacy of doxorubicin, vincristine through potentiation of apoptosis in both MCF-7-R and A549-R at relatively noncytotoxic concentrations in vitro. Mechanistic studies showed that 5-N-formylardeemin inhibited the expression of MDR-1 (P-gp) and increased the intracellular accumulation of cytotoxic drugs in the MDR cells, suggesting that 5-N-formylardeemin reverses MDR activities through inhibiting MDR-1 expression. Interestingly, 5-N-formylardeemin also sensitized the parent wild-type cancer cells toward these chemotherapeutic agents to various extents. Importantly, in vivo studies demonstrated that 5-N-formylardeemin significantly improved the therapeutic effects of doxorubicin in nude mice bearing A549-R xenografts, which was associated with reduced expression of MDR-1 protein level and increased apoptosis in tumor tissues. These results underscore 5-N-formylardeemin as a potential sensitizer for chemotherapy against multidrug resistant cancers.

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Synthesis and ABCG2 inhibitory evaluation of 5-N-acetylardeemin derivatives

Hayashi

Tsukioka

Inoue

et al. 2015

Bioorganic & Medicinal Chemistry

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MDR Reversal by Deprenylated Tetracyclic and Hexacyclic Analogues of N-Acetylardeemin: Confirmation of the Ardeemin Pharmacophore

Cited by 8 publications

References 13 publications

Antitumor Activity of Quinazolinone Alkaloids Inspired by Marine Natural Products

Antitumor Activity of Quinazolinone Alkaloids Inspired by Marine Natural Products

Reversal of multidrug resistance in vitro and in vivo by 5-N-formylardeemin, a new ardeemin derivative

Synthesis and ABCG2 inhibitory evaluation of 5-N-acetylardeemin derivatives

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