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. 2018 Sep 30;3(9):11469-11476.
doi: 10.1021/acsomega.8b01987. Epub 2018 Sep 20.

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

Carla E Brown  1 , Tiffany Kong  1 , James F Britten  1 , Nick H Werstiuk  1 , James McNulty  1 , Leonardo D'Aiuto  2 , Matthew Demers  2 , Vishwajit L Nimgaonkar  2
Affiliations

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

Carla E Brown et al. ACS Omega. .

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.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
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
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
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
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
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
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).
See this image and copyright information in PMC

References

    1. Jin Z. Amaryllidaceae and Sceletium Alkaloids. Nat. Prod. Rep. 2013, 30, 849–868. 10.1039/c3np70005d. - DOI - PubMed
    1. Bastida J.; Berkov S.; Pigni N. B.; de Andrade J. P.; Martínez V.; Codina C.; Viladomat F.. Chemical and Biological Aspects of Amaryllidaceae Alkaloids. In Recent Advances in Pharmaceutical Sciences; Muñoz-Torrero D., Ed.; 2011; pp 65–100.
    1. Evidente A.; Kireev A.; Jenkins A.; Romero A.; Steelant W.; Van Slambrouck S.; Kornienko A. Biological Evaluation of Structurally Diverse Amaryllidaceae Alkaloids and Their Synthetic Derivatives: Discovery of Novel Leads for Anticancer Drug Design. Planta Med. 2009, 75, 501–507. 10.1055/s-0029-1185340. - DOI - PMC - PubMed
    1. Martin S. F.The Amaryllidacea Alkaloids. In The Alkaloids; Brossi A., Ed.; Cambridge, Mass., 1987; Vol. 30, pp 251–376.
    1. Ghavre M.; Froese J.; Pour M.; Hudlicky T. Synthesis of Amaryllidaceae Constituents and Unnatural Derivatives. Angew. Chem., Int. Ed. 2016, 55, 5642–5691. 10.1002/anie.201508227. - DOI - PubMed