title: Another Look at Pyrroloiminoquinone Alkaloids-Perspectives on Their Therapeutic Potential from Known Structures and Semisynthetic Analogues.
abstract: This study began with the goal of identifying constituents fromZyzzya fuliginosaextracts that showed selectivity in our primary cytotoxicity screen against the PANC-1 tumor cell line. During the course of this project, which focused on sixZ.fuliginosasamples 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/zions 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 IC50data 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 IC50values 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 of9whose IC50= 120 nM vs. that of15having IC50= 8.6 nM.
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA 95064, USA. linsheng2014cn@gmail.com.|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. linsheng2014cn@gmail.com.
authors.forename: Sheng
authors.initials: S
authors.lastname: Lin
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA 95064, USA. emccaule@ucsc.edu.
authors.forename: Erin P
authors.initials: EP
authors.lastname: McCauley
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA 95064, USA. nlorigro@ucsc.edu.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Lorig-Roach
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA 95064, USA. ktenney@ucsc.edu.
authors.forename: Karen
authors.initials: K
authors.lastname: Tenney
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA 95064, USA. cnaphen@gmail.com.
authors.forename: Cassandra N
authors.initials: CN
authors.lastname: Naphen
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA 95064, USA. aimeiyang@163.com.|School of Life Science and Engineering, Lanzhou University of Technology, Lanzhou 730050, China. aimeiyang@163.com.
authors.forename: Ai-Mei
authors.initials: AM
authors.lastname: Yang
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA 95064, USA. tyler.johnson@dominican.edu.
authors.forename: Tyler A
authors.initials: TA
authors.lastname: Johnson
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA 95064, USA. taj_@chemistry.ucsc.edu.
authors.forename: Thalia
authors.initials: T
authors.lastname: Hernadez
authors.affiliation: Department of Internal Medicine, Division of Hematology and Oncology, Henry Ford Hospital, Detroit, MI 48202, USA. rrattan1@hfhs.org.
authors.forename: Ramandeep
authors.initials: R
authors.lastname: Rattan
authors.affiliation: Department of Internal Medicine, Division of Hematology and Oncology, Henry Ford Hospital, Detroit, MI 48202, USA. FVALERI1@hfhs.org.
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Valeriote
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA 95064, USA. pcrews@ucsc.edu.
authors.forename: Phillip
authors.initials: P
authors.lastname: Crews
mesh_terms: D000470:Alkaloids / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D011161:Porifera / Q000737:chemistry; D047608:Pyrroloiminoquinones / Q000737:chemistry* / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods; D013329:Structure-Activity Relationship
chemical_list: D000470:Alkaloids; D047608:Pyrroloiminoquinones
keywords: MS-MS fragmentation profiling; PANC-1 and OVCAR-5 cytotoxicity; Zyzzya fuliginosa; makaluvamine; marine sponge