Preparation and in vitro antifungal activities of some quinolizidine derived hemiaminals and .beta.-tert-amino sulfides

Abstract

New alpha-thiohemiaminals, 7alpha-phenylthio-7-epideoxynupharidin-6-ol, the diasteriomeric 7beta-phenylthiodeoxy-nupharidin-6-ol, and 3-methyl-3-methylthio-4-hydroxyquinolizidine, were prepared and reduced to the corresponding beta-tert-amino sulfides. The configuration at C-7 of the beta-tert-amino sulfides was determined by observing the direction of the solvent-induced shift of the C-7 methyl proton resonance. The configuration at C-7 of the new alpha-thiohemiaminals was established by correlations with the beta-tert-amino sulfides and confirmed, in the case of the deoxynupharidine derivatives, by circular dichroism and ascertaining the sterochemistry of deuteride incorporation upon sodium borodeuteride reduction of the alpha-thiohemiaminal. The in vitro antifungal activities of six compounds possessing the quinolizidine skeleton, including all the newly synthesized compounds as well as some previously reported ones, and amphotericin B were tested against several human pathogenic fungi. Besides amphotericin B, only the two deoxynupharidine alpha-thiohemiaminals were active, especially against Histoplasma capsulatum and Blastomyces dermatitidis. The observations indicate activity is derived from the 3-furyl group and the functionality from which alpha-thioimmonium ions can be produced.

Intramolecular iminium ion-sulfide charge-transfer association: a recurring theme in the study of thiaspirane alkaloids

“…The arylthio hemiaminal 23 reduced with lithium aluminum deuteride in the much less polar ether gave tertiary amines 24 and 25 in a 50:50 ratio while a similar aryl thiohemiaminal treated with sodium borodeuteride in methanol underwent stereospecific reduction, giving a tertiary amine possessing 85% equatorial deuterium at C-6. 24 To this point, the results reviewed in this section indicate the reduction of the -thio hemiaminals by sodium borodeuteride in methanol is a stereospecific process dependent on the configuration of an adjacent sulfur-bearing carbon. This is not the case for the homologous d-thio hemiaminals, at least not those incorporated in the thiaspirane skeleton.…”

Synthesis and Sulfur Electrophilicity of the Nuphar Thiaspirane Pharmacophore

“… 8 Simplified analogues that replace the thioether with a hydroxyl are also reported to lose all activity in fungicidal experiments. 14 One explanation put forth for these structural requirements is the enhanced stability of the iminium adjacent to a thioether in 6-hydroxydimers ( Figure 1 b), 15 − 17 which may allow this otherwise strong carbon electrophile to penetrate the cell and reach a specific target. 2 In contrast, the electrophilic promiscuity of the unstabilized iminium/hemiaminal of 6′-hydroxy dimers is thought to prevent access to a specific target.…”

“…Cytotoxicity assays indicate that a hemiaminal adjacent to the tert -alkyl thioether (C6) is necessary for induction of apoptosis, whereas a thioether adjacent to a quaternary center (C6′) displays low potency. , For example, 6-OH-TNL ( 2b , Figure a) is strongly apoptotic below 1 μM, whereas 6′-OH-TNL ( 2c ) is completely inactive at 10 μM . Simplified analogues that replace the thioether with a hydroxyl are also reported to lose all activity in fungicidal experiments . One explanation put forth for these structural requirements is the enhanced stability of the iminium adjacent to a thioether in 6-hydroxydimers (Figure b), − which may allow this otherwise strong carbon electrophile to penetrate the cell and reach a specific target .…”