Antineoplastic Agents 491.¹ Synthetic Conversion of Aaptamine to Isoaaptamine, 9-Demethylaaptamine, and 4-Methylaaptamine

Abstract

Aaptamine (1) was used as starting material for synthetic transformation to isoaaptamine (2), 9-demethylaaptamine (5), and 4-methylaaptamine (6). A general method for the selective O-demethylation of such 1H-benzo[de][1,6]-naphthyridine (1) marine sponge constituents at position C-9 has been developed. Selective O-demethylation of aaptamine (1) and 1-methylaaptamine (11) with 48% hydrobromic acid led to 9-demethylaaptamine (5) and isoaaptamine (2), respectively. A selection of other aaptamine derivatives were synthesized, and their structures were unambiguously determined by X-ray methods. In addition, their cancer cell growth inhibitory properties were evaluated against the murine P388 lymphocytic cell line and a minipanel of human cancer cell lines. Evaluation as inhibitors of the PKC signal transduction pathway and against a selection of microorganisms was also undertaken. Aaptamine derivatives 3 and 5 had broad-spectrum antimicrobial activities.

Aaptamine and related products. Their isolation, chemical syntheses, and biological activity

“…Pettit et al 126 synthesized half of these 16 possible methyl-derivatives in order to explore their anticancer structure-activity relationships.…”

“…Hystatin 1 (163), a prodrug of isoaaptamine (2) retained part of the antimicrobial activity of the parent compound. 126 On the other hand, N-benzyl derivatives 166 and 167 were marginally active against Streptococcus pneumoniae and Neisseria gonorrheae (IC 50 ¼64 mg/mL), whilst 164 and 165 inhibited the clinically important microorganisms Micrococcus luteus (IC 50 ¼0.5-2 mg/mL) and N. gonorrheae (IC 50 ¼0.25-4 mg/mL). 125 Pettit has also found antifungal activity against Cryptococcus neoformans 125 in compound 165, whilst 9-demethylaaptamine (3) and 8,9-bisdemethylaaptamine (5) were active against Candida albicans and C. neoformans (IC 50 ¼32-64 mg/mL).…”

Synthesis of new carbon‐11‐labeled 7‐aroyl‐aminoindoline‐1‐sulfonamides as potential PET agents for imaging of tubulin polymerization in cancers

“…In order to prepare the demethylated precursors, we envisioned that precursor compounds 11a-d could be prepared by O-demethylation of target compounds 4a-d. A variety of protocols were screened for this purpose including protic acid (HBr), 8 Lewis acids (BBr 3 , AlCl 3 /EtSH), 9,10 and base (EtSNa). 11 However, in all cases, an intractable red solid that could not be characterized or a demethylated product with very low yield was obtained.…”

Regioselective Synthesis of 3‐Hydroxyorthanilic Acid and Its Biotransformation into a Novel Phenoxazinone Dye by Use of Laccase

“…Alternatively, simultaneous deprotection of both functions could be achieved from precursor 9 by heating in aqueous HBr [31] solution. The final target 3-HOA was obtained with an overall yield of 50 %.…”