Inspirations from Nature: Biomimetic Synthesis of Bioactive Marine Natural Products

Abstract

Marine natural products are becoming widely recognised as novel sources of drug leads. Their structural complexity has attracted synthetic chemists to explore new synthetic strategies and reagents. More recently, biosynthetic considerations of natural product has led to the proposal of biogenetic precursors that may lead to a biomimetic synthesis of a particular family of compounds. If successful, biomimetic syntheses may lead to the synthesis of multiple compounds in a family of natural products from simple precursors in a short, stepwise fashion. Thiaplidiaquinone A (2.1) and B (2.2) were synthesised in a 5-step biomimetic reaction sequence where the dimeric core was constructed by allowing a simple benzoquinone to dimerise and cyclise in the presence of base. The installation of the dioxothiazine ring system allowed for the synthesis of the two natural products alongside their corresponding dioxothiazine regioisomers 2.58 and 2.59. Cytotoxicity bioassays revealed that the position of the geranyl sidechains determined the mode of cell death (necrosis versus apoptosis) whereas the dioxothiazine ring regulated the potency of the compounds. The synthesised regioisomers were found to be more potent than their natural product counterparts with one, 2.58, exhibiting sub-panel selectivity towards melanoma cancer cell lines and was selected for acute toxicity testing by the NCI. A biomimetic synthesis of pyridoacridine alkaloids amphimedine (3.3), deoxyamphimedine (3.16) and demethyldeoxyamphimedine (3.11) from the structurally simpler styelsamine D (3.13) was developed. Addition of formaldehyde to the proposed biosynthetic precursor, styelsamine D, gave the two natural products 3.11 and 3.16 in a one pot synthesis where subsequent oxidation of 3.16 gave amphimedine. It was found that pre-functionalisation of the dopamine precursor to styelsamine D allowed for the synthesis of N-ethyl analogues of amphimedine and deoxyamphimedine as well as an N-benzyl analogue of deoxyamphimedine. Biomimetic considerations of the neoamphimedine, arnoamine and alpkinidine scaffold were also investigated and the results highlighted herein. Biological evaluation of the amphimedine, deoxyamphimedine and demethyldeoxyamphimedine at the NCI identified deoxyamphimedine as a strong cytotoxic agent, exhibiting sub-panel selectivity towards central nervous system cancer cell lines.