Azaviridins as New Scaffolds
for the Development of PI-3K Inhibitors

Teather J. Sundstrom; Dennis L. Wright

doi:10.1055/s-0030-1259026

LETTER

Azaviridins as New Scaffolds for the Development of PI-3K Inhibitors

Teather J. Sundstrom, Dennis L. Wright*
Department of Pharmaceutical Sciences, University of Connecticut, Storrs CT, 06269, USA
Fax: +1(860)4866857; e-Mail: dennis.wright@uconn.edu;

Abstract

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Abstract

We have designed a new class of non-natural furanosteroids to serve as more chemically stable analogues of the viridins, potent inhibitors of PI-3K. Central to the design is the incorporation of a nitrogen atom into the steroidal ring system to attenuate the activity of the electrophilic 2,4-diacylfuran common to these natural products. In this manuscript, we describe our initial synthetic studies on this ring system and the preparation of key intermediates for analogue generation.

Key words

natural products - heterocycles - furans - amination - palladium

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References

References and Notes

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Selected Characterization Data for Compound 18
^¹H NMR (500 MHz, CD₃OD): δ = 9.10 (s, 1 H), 8.29 (d, J = 8.8 Hz, 1 H), 8.25 (s, 1 H), 7.84 (d, J = 8.8 Hz, 1 H), 4.43 (q, J = 7.1 Hz, 2 H), 1.44 (t, J = 7.1 Hz, 3 H). ^¹³C NMR (125 MHz, CD₃OD): δ = 167.5, 152.6, 150.4, 133.2, 129.8, 129.7, 125.9, 125.3, 119.9, 119.5, 103.4, 79.6, 62.6, 14.8. IR (KBr): 3087, 2964, 1633, 1598, 1573 cm^-¹. HRMS-FAB: m/z calcd for C₁₄H₁₁BrNO₆ [M + H]⁺: 335.9866; found: 335.9866.

Selected Characterization Data for Compound 20
^¹H NMR (500 MHz, CDCl₃): δ = 9.26 (d, J = 1.9 Hz, 1 H), 8.29 (dd, J = 2.0 Hz, 1 H), 7.52 (s, 1 H), 7.35 (d, J = 8.9 Hz, 1 H), 6.63 (dt, J = 2.2, 10.1 Hz, 1 H), 6.00 (dt, J = 3.3, 10.1 Hz, 1 H), 4.99 (s, 2 H), 4.42 (q, J = 7.1 Hz, 2 H), 1.44 (t, J = 7.1 Hz, 3 H). ^¹³C NMR (125 MHz, CDCl₃): δ = 166.2, 164.7, 142.0, 141.8, 137.1,136.5, 132.4,130.2, 127.2, 124.5, 123.1, 115.9, 113.6, 111.9, 61.4, 46.6, 14.7. ESI-HRMS: m/z calcd for C₁₇H₁₄NO₄ [M + H]⁺: 296.0923; found: 296.0917.