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Mar. Drugs 2017, 15(4), 98; doi:10.3390/md15040098

Another Look at Pyrroloiminoquinone Alkaloids—Perspectives on Their Therapeutic Potential from Known Structures and Semisynthetic Analogues

1
Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA 95064, USA
2
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
3
School of Life Science and Engineering, Lanzhou University of Technology, Lanzhou 730050, China
4
Department of Internal Medicine, Division of Hematology and Oncology, Henry Ford Hospital, Detroit, MI 48202, USA
*
Author to whom correspondence should be addressed.
Academic Editors: Yu-Dong Zhou, Dale G. Nagle and Anake Kijjoa
Received: 26 January 2017 / Revised: 15 March 2017 / Accepted: 27 March 2017 / Published: 29 March 2017
(This article belongs to the Special Issue Marine Drugs as Antitumour Agents 2017)
View Full-Text   |   Download PDF [2631 KB, uploaded 29 March 2017]   |  

Abstract

This study began with the goal of identifying constituents from Zyzzya fuliginosa extracts that showed selectivity in our primary cytotoxicity screen against the PANC-1 tumor cell line. During the course of this project, which focused on six Z. fuliginosa samples collected from various regions of the Indo-Pacific, known compounds were obtained consisting of nine makaluvamine and three damirone analogues. Four new acetylated derivatives were also prepared. High-accuracy electrospray ionization mass spectrometry (HAESI-MS) m/z ions produced through MS2 runs were obtained and interpreted to provide a rapid way for dereplicating isomers containing a pyrrolo[4,3,2-de]quinoline core. In vitro human pancreas/duct epithelioid carcinoma (PANC-1) cell line IC50 data was obtained for 16 compounds and two therapeutic standards. These results along with data gleaned from the literature provided useful structure activity relationship conclusions. Three structural motifs proved to be important in maximizing potency against PANC-1: (i) conjugation within the core of the ABC-ring; (ii) the presence of a positive charge in the C-ring; and (iii) inclusion of a 4-ethyl phenol or 4-ethyl phenol acetate substituent off the B-ring. Two compounds, makaluvamine J (9) and 15-O-acetyl makaluvamine J (15), contained all three of these frameworks and exhibited the best potency with IC50 values of 54 nM and 81 nM, respectively. These two most potent analogs were then tested against the OVCAR-5 cell line and the presence of the acetyl group increased the potency 14-fold from that of 9 whose IC50 = 120 nM vs. that of 15 having IC50 = 8.6 nM. View Full-Text
Keywords: makaluvamine; Zyzzya fuliginosa; marine sponge; MS-MS fragmentation profiling; PANC-1 and OVCAR-5 cytotoxicity makaluvamine; Zyzzya fuliginosa; marine sponge; MS-MS fragmentation profiling; PANC-1 and OVCAR-5 cytotoxicity
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MDPI and ACS Style

Lin, S.; McCauley, E.P.; Lorig-Roach, N.; Tenney, K.; Naphen, C.N.; Yang, A.-M.; Johnson, T.A.; Hernadez, T.; Rattan, R.; Valeriote, F.A.; Crews, P. Another Look at Pyrroloiminoquinone Alkaloids—Perspectives on Their Therapeutic Potential from Known Structures and Semisynthetic Analogues. Mar. Drugs 2017, 15, 98.

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