5 research outputs found
Another Look at Pyrroloiminoquinone Alkaloids-Perspectives on Their Therapeutic Potential from Known Structures and Semisynthetic Analogues
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
La Correspondencia de España : diario universal de noticias: Año XXV Número 6073 - 1874 julio 18
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
Biosynthetic Products from a Nearshore-Derived Gram-Negative Bacterium Enable Reassessment of the Kailuin Depsipeptides
Sampling of California nearshore
sediments resulted in the isolation
of a Gram-negative bacterium, <i>Photobacterium halotolerans</i>, capable of producing unusual biosynthetic products. Liquid culture
in artificial seawater-based media provided cyclic depsipeptides including
four known compounds, kailuins B–E (<b>2</b>–<b>5</b>), and two new analogues, kailuins G and H (<b>7</b> and <b>8</b>). The structures of the new and known compounds
were confirmed through extensive spectroscopic and Marfey’s
analyses. During the course of these studies, a correction was made
to the previously reported double-bond geometry of kailuin D (<b>4</b>). Additionally, through the application of a combination
of derivatization with Mosher’s reagent and extensive <sup>13</sup>C NMR shift analysis, the previously unassigned chiral center
at position C-3 of the β-acyloxy group of all compounds was
determined. To evaluate bioactivity and structure–activity
relationships, the kailuin core (<b>13</b>) and kailuin lactam
(<b>14</b>) were prepared by chiral synthesis using an Fmoc
solid-phase peptide strategy followed by solution-phase cyclization.
All isolated compounds and synthetic cores were assayed for solid
tumor cell cytotoxicity and showed only minimal activity, contrary
to other published reports. Additional phenotypic screenings were
done on <b>4</b> and <b>5</b>, with little evidence of
activity