Brent S. Lindsay

Structural requirements for biological activity of the marine alkaloid ascididemin

Comparison of the biological activities observed for ascididemin (2) and synthetic precursors/analogs has established the importance of N-8 in ring A, and a completed ring E, to topoisomerase II enzyme inhibition, human tumor cytotoxicity and antifungal/antibacterial properties. The results also suggest the presence of multiple mechanisms of toxicity by 2 towards mammalian cell systems.

Structural Studies of Cytotoxic Marine Alkaloids: Synthesis of Novel Ring-E Analogues of Ascididemin and their in vitro and in vivo Biological Evaluation

Abstract The cytotoxic marine alkaloid ascididemin and various pyridine ring-E analogues have been synthesised in an attempt to determine the pharmaceutical utility and structure-activity requirements for the parent alkaloid. All compounds synthesised were evaluated in a wide range of biological screens for selective cytotoxicity, antiviral, antifungal and antimicrobial properties. Many analogues exhibited selective cytotoxicity to human solid tumour cell-lines in vitro, with one also exhibiting moderate antitumour activity in in vivo xenograft assays.

Efficient and Convenient Pyridine Ring-E Formation of the Cytotoxic Marine Alkaloid Ascididemin and Related Analogues.

Abstract Conversion of tetracyclic quinone 1 to the cytotoxic pentacyclic alkaloid ascididemin (2) in 80% yield is achieved by reaction with paraformaldehyde and ammonium chloride in refluxing acetic acid. High yielding annelations are aiso observed for the related analogues N-8 deaza ascididemin (3) and kuanoniamine A (4).

A Convenient New Route to 4-Substituted Benzo[de][3,6]Phenanthrolin-6(6H)-Ones: Important Intermediates in the Synthesis of Ring-A Analogues of the Cytotoxic Marine Alkaloid Ascididemin

Abstract 4-ethylthio- and 4-(4″-methylphenylthio)benzo[de][3,6]phenanthrolin-6(6H)-one have been synthesised in 4 steps from benzoquinone and then readily converted to the 4-amino (6d) and 4-methoxy (6c) analogues by nucleophilic substitution. Further elaboration of 6d leads to the synthesis of 11-hydroxyascididemin, which we have found to exhibit antiviral activity in vitro.

Crystal structure of the cytotoxic marine alkaloid 2-bromoleptoclinidinone

Abstract2-Bromoleptoclinidinone methanol solvate, C18H8BrN3O·CH4O, crystallizes in the orthorhombic space group Pbca with a = 15.7013(2), b = 7.3308(1), and c = 26.9326(1) Å. The molecule is essentially planar, with the largest deviations occurring at bromine (−0.21 Å), carbonyl oxygen O(l) (+0.19 Å) and in ring-A (C(9) −0.15 Å, C(10) −0.15 Å). Methanol occupies the 1,10-phenanthroline-like metal binding site of the title compound.

11-Methylpyrido[2,3-b]acridine-5,12-dione

The title molecule, C17H10N2O2, is a synthetic precursor to the cytotoxic marine alkaloid ascididemin and is also structurally related to cleistopholine, a plant-derived antifungal agent. The molecule was found to be essentially planar with the only significant deviations from planarity being for the quinone O atoms.