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

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

References and Notes

• 1 Fruman DA. Meyers RE. Cantley LC. Ann. Rev. Biochem.  1998,  67:  481 
• 2a Sundstrom T. Anderson A. Wright DL. Org. Biomol. Chem.  2009,  7:  840 
• 2b Samuels Y. Wang Z. Bardelli A. Silliman N. Ptak J. Szabo S. Yan H. Gazdar A. Powell SM. Riggins GJ. Willson JKV. Markowitz S. Kinzler KW. Vogelstein B. Velculescu VE. Science  2004,  304:  554 
• 2c Vivanco I. Sawyers CL. Nat. Rev. Cancer  2002,  2:  489 
• 2d Hu L. Hofmann J. Jaffe RB. Clin. Cancer Res.  2005,  11:  8208 
• 2e Cully M. You H. Levine AJ. Mak TW. Nat. Rev. Cancer  2006,  6:  184 
• 3 Norman BH. Shih C. Toth JE. Ray JE. Dodge JA. Johnson DW. Rutherford PG. Schultz RM. Worzalla JF. Vlahos CJ. J. Med. Chem.  1996,  39:  1106 
• 4 Schultz RM. Merriman RL. Andis SL. Bonjouklian R. Grindey GB. Rutherford PG. Gallegos A. Massey K. Powis G. Anticancer Res.  1995,  15:  1135 
• 5 Wright DL. Robotham CV. Aboud K. Tetrahedron Lett.  2002,  43:  953 
• 6 Drahl C. Cravatt BF. Sorensen EJ. Angew. Chem. Int. Ed.  2005,  44:  5788 
• 7 Walker EH. Pacold ME. Perisic O. Stephens L. Hawkins PT. Wymann MP. Williams RL. Mol. Cell  2000,  6:  909 
• 8 Anderson EA. Alexanian EJ. Sorensen EJ. Angew. Chem. Int. Ed.  2004,  43:  1998 
• 9 Des Abbayes H. Alper H. J. Am. Chem. Soc.  1977,  99:  98 
• 10 Begouin A. Hesse S. Queiroz MRP. Kirsch G. Synthesis  2006,  2794 
• 11 Mee SPH. Lee V. Baldwin JE. Cowley A. Tetrahedron  2004,  60:  3695 

12

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.

13

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.