Studies on Cancer Preventive and its related bioactive constituents of Monascus purpureus NTU 568 Fermented Products
Date Issued
2011
Date
2011
Author(s)
Hsu, Ya-Wen
Abstract
In our previous reports, the red mold rice (RMR) fermented by Monascus purpureus NTU 568, mutated by UV irradiation, have been proved for hypolipidemic effects, the regulation of obesity-related factors, and the amelioration of the impairment of memory ability in vivo. Moreover, the ethanol extracts of M. purpureus NTU 568 fermented rice also could mitigate oral carcinogenesis in 7,12-dimethyl-1,2-bena[a]anthracene (DMBA)-induced oral tumor as well as reduce tumor progression of Lewis lung cancer.
Monascus pigments compose of yellow, orange and red pigments which belonged to an azaphilone skeleton, and have been reported to possess anti-inflammantory and anticancer activities. Consequently, the aims of the thesis are to study the bioactive chemical constituents from M. purpureus NTU 568 fermented products and further evaluate their anti-proliferative, anti-inflammatory and anti-oxidative activities of isolates.
By column chromatography and high performance liquid chromatography, fourteen (1~14), eight (1, 2, 15~20) azaphilone derivatives and two siderophore skeleton compounds (33 and 34), were isolated from methanol extracts, acetone extracts, and the 50% ethanol extracts of red mold dioscorea (RMD), respectively. Moreover, six azaphilone derivatives (21-26) were derived from yellow pigments, ankaflavin (1) and monascin (2), via chemical reaction. Four azaphione derivatives (27-30) and two known red pigments, monascorubramine (31) and rubropunctamine (32), were also acquired by a short semi-synthesis of orange pigments, monascorubrin (15) and rubropunctatin (16). Structural elucidation of isolated compounds was based on mass, infrared (IR), ultraviolet (UV), and nuclear magnetic resonance (1H-NMR, 13C-NMR, COSY, HMQC, and HMBC) spectroscropic analyses. Of the above mentioned twenty-two isolates, including monaphilone A (3), monaphilone B (4), monaphilone C (5), monapurpyridine A~B (9~10), monapurfluore A (13), monapurfluore B (14), monaphilol A (17), monaphilol B (18), monaphilol C (19), and monaphilol D (20) were verified as new compounds.
Compounds 1-32 were further evaluated for their inhibitory effects on the proliferation against human tumor cell lines, HEp-2 (human laryngeal carcinoma) and WiDr (human colon adenocarcinoma), as well as MCF-7 (human breast adenocarcinoma). Bioactive data showed that most of isolates (1-32) had moderate anti-proliferative activities (IC50 : 20 to 80 μM) and monaphilol A-D (17-20) had potent anti-proliferative effect (IC50 : 8 to 15 μM). Monascin (2) exhibited a selective inhibitory effect toward HEp-2, while FK-17-P2b1 (6), monasflure A (13) and monasflure B (12) showed significant inhibitory effects agaist MCF-7. For the structure-activity relationship (SAR) studies of orange pigments (15, 16) and their derivatives (17-20 & 27-32), the anti-proliferative activities of compounds 17-20 with hydroxyl group at C-8 show 4- to 7- fold higher than that of compounds 15 and 16 with ketone group at C-8. However, the anti-proliferative activities of compounds 27-30 were less than compounds 17-20, duo to the hydroxyl groups substituted by ketone groups at C-8 and C-14.
Moreover, compounds 1-14, except for monascin (2), monasphilone C (5) and FK-17-P2b1 (6), exhibited promising anti-NO production on LPS-stimulated RAW264.7 macrophages compared with the positive control, quercetin (IC50 : 13.2 μM). Monapurpyridine C (10) showed cytotoxic phenomenon for RAW264.7 cells at 10-15 μg/mL. However, monaphilol A-D (17-20) could reduce LPS-stimulated NO production completely at 5 μg/mL; whereas, they exhibited cytotoxic effects for RAW264.7 cells at 10 μg/mL. Dimerumic acid (DMA) and deferricoprogen (DFC), were isolated from the 50% ethanol extracts of M. purpureus NTU 568 fermented red mold rice (RMR) by antioxidant guided fractionation method. DMA and DFC showed potent DPPH free radical scavenging activities with IC50 value of 16 and 15 μg/mL, respectively. The concentrations of DMA and DFC in RMR were determined as 0.85 and 3.00 mg/g employing HPLC analysis.
In this study, twenty-one azaphilone derivatives possessing anti-inflammatory and anti-proliferative effects, as well as two major natural anti-oxidative compounds were isolated and characterize from M. purpureus NTU 568 fermented products. The investigation of chemopreventive mechanism of these bioactive isolates remain to be established. We hope that the potential azaphilone analogues isolated from Monascus purpureus NTU 568 fermented products will be developed as a functional food of cancer chemoprevention.
Subjects
Monascus purpureus
anti-proliferative
anti-inflammatory
anti-oxidative
azaphilone
monaphilone
monaphilol
SDGs
Type
thesis
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