Asymmetric Entry into 10 b-aza-Analogues of Amaryllidaceae Alkaloids Reveals a Pronounced Electronic Effect on Antiviral Activity

Abstract

Development of a chiral pool-based synthesis of 10b-aza-analogues of biologically active Amaryllidaceae alkaloids is described, involving a concise reductive amination and condensation sequence, leading to ring-B/C-modified, fully functionalized ring-C derivatives. Differentiated anticancer and antiviral activities of these analogues are presented. Despite complete conformational and functional group overlap, the 10b-aza-analogues have diminished anticancer activity and no antiviral activity. These unprecedented electronic effects suggest a possible role for π-type secondary orbital interactions with the biological target.

Figure 1

(A) Structure of representative Amaryllidaceae constituents galanthamine (1), pancratistatin (2), trans-dihydronarciclasine (3), and trans-dihydrolycoricidine (4) and (B) general quinazolidinone core structure (5), the novel hybrid heterocycle 6 and proposed retrosynthesis from an anthranilamide 7, and pentose l-arabinose (8).

Scheme 1. l-Arabinose (8) Selectively Protected at C5 Alcohol as TBS-Ether Was Coupled to Anthranilamide (7b) via a Reductive Amination: (a) TBS-Cl, Pyridine; (b) NaCNBH₃, MeOH; and (c) Ac₂O, DIPEA, DCM

Scheme 2. Conversion of 11 via Deprotection, Oxidation, and Ring Closure to the Quinazolinone–Lycorane Hybrids15 and 16: (d) HF·Py, THF; (e) IBX, DMSO, 60 °C; and (f) K₂CO₃, MeOH; Bottom: ORTEP Diagram of 14

Scheme 3. Synthesis of 21 and 22 from l-Arabinose (8) and 3,4-Methylenedioxyanthranilamide (7a): (a) TBS-Cl, Pyridine; (b) NaCNBH₃, MeOH; (c) Ac₂O, DIPEA, DCM; (d) HF·Py, THF; (e) IBX, DMSO, 60 °C; and (f) K₂CO₃, MeOH

Figure 2

Anti-HSV-1 activity of synthetic compounds 4 and 19–22 in neurons infected with HSV-1 expressing EGFP linked to the ICP90 promoter at MOI = 0.3; Y-axis depicts GFP+ cell percentage. Vehicle = uninfected and viral-infected untreated cells and ACV = acyclovir-positive control.

Figure 3

DFT-optimized molecular geometry (B3PW91/6-311+G(2d,p)) of compounds 4 (top left) and 21 (top right) illustrating identical ring-C phenanthridone-type conformations in contrast with diastereomer 22 (bottom).