Synthesis and Biological Evaluation of Nicotinamide Adenine Dinucleotides Analogues as Inhibitors of CD38

doi:10.3969/j.issn.0251-0790.2012.06.018

Abstract

Abstract: CD38 is the main mammalian ADP-ribosyl cyclase and a signaling enzyme responsible for catalyzing the synthesis of Ca²⁺-messengers and plays a critical role in a wide range of physiological functions. It is of great interest to develop specific and generally applicable inhibitors of CD38. Fluoro-substituted nicotina-mide adenine dinucleotides(NAD), such as ara-F NMN and ara-F NAD, are catalysis-dependent inhibitors of CD38 and are often used as probes for investigating the function of CD38. For understanding the effect of fluoro-substitution on activity in more detail and discovery of active inhibitors of CD38, compounds 2a—2c were synthesized and their inhibition against the hydrolysis activities of CD38 were evaluated. The syntheses were performed by starting from the corresponding fluoro-substituted sugar, then followed by coupling with nicoti-namide, regio-selective 5'-phosphorylation and condensation with adenosine monophosphate, successively. All target compounds were purified by HPLC and characterized by NMR and HRMS. Two compounds showed strong inhibitions, especially 2'-deoxy-2'-fluororibonofuranosyl which gave activity with IC₅₀ of 0.056 μmol/L and was two orders of magnitude higher than positive control ara-F NAD. The results also showed that the activity was greatly affected by the number and the position of fluorine atom on the sugar ring, as well as the configuration of the inhibitors. The detailed biological investigation and structure-activity relationship are underway.

Key words: Nicotinamide adenine dinucleotides(NAD), Fluoro-substituted NAD analogue, CD38 inhibitor, Biological activity

CLC Number:

O621

TrendMD:

CHEN Zhe, KWONG Anna Ka-Yee, YANG Zhen-Jun, ZHANG Liang-Ren, LEE Hon Cheung, ZHANG Li-He. Synthesis and Biological Evaluation of Nicotinamide Adenine Dinucleotides Analogues as Inhibitors of CD38[J]. Chem. J. Chinese Universities, 2012, 33(06): 1226.

References

[1] Lesiak K., Watanabe K. A., Majumdar A., Seidman M., Vanderveen K., Goldstein B. M., Pankiewicz K. W.. J. Med. Chem.[J], 1997, 40(16): 2533—2538 [2] Rejman D., Olesiak M., Chen L. Q., Patterson S. E., Wilson D., Jayaram H. N., Hedstrom L., Pankiewicz K. W.. J. Med. Chem.[J], 2006, 49(16): 5018—5022 [3] Pankiewicz K. W., Patterson S. E., Black P. L., Jayaram H. N., Risal D., Goldstein B. M., Stuyver L. J., Schinazi R. F.. Curr. Med. Chem.[J], 2004, 11(7): 887—900 [4] Migaud M. E., Pederick R. L., Bailey V. C., Potter B. V. L.. Biochemistry[J], 1999, 38(28): 9105—9114 [5] Choe C., Lardong K., Gelderblom M., Ludewig P., Leypoldt F., Koch-Nolte F., Gerloff C., Magnus T.. PLoS ONE[J], 2011, 6(5): e19046 [6] Dong M., Si Y. Q., Sun S. Y., Pu X. P., Yang Z. J., Zhang L. R., Zhang L. H., Leung F. P., Lam C. M., Kwong A. K., Yue J., Zhou Y., Kriksunov I. A., Hao O., Lee H. C.. Org. Biomol. Chem.[J], 2011, 9(9): 3246—3257 [7] Yue J. B., Wei W. J., Lam C. M. C., Zhao Y. J., Dong M., Zhang L. R., Zhang L. H., Lee H. C.. J. Biol. Chem.[J], 2009, 284(43): 29335—29342 [8] Sauve A. A., Schramm V. L.. Biochemistry[J], 2000, 41(26): 8455—8463 [9] Zhang H. M., Graeff R., Chen Z., Zhang L., Zhang L. R., Zhang L. H., Lee H. C., Hao Q.. J. Mol. Biol.[J], 2011, 405(4): 1070—1078 [10] Jiang H., Congleton J., Liu Q., Merchant P., Malavasi F., Lee H. C., Hao Q., Yen A., Lin H. N.. J. Am. Chem. Soc.[J], 2009, 131(5): 1658—1659 [11] Ma J. A., Cahard D.. Chem. Rev.[J], 2008, 108(9): PR1—PR43 [12] Hagmann W. K.. J. Med. Chem.[J], 2008, 51(15): 4359—4369 [13] Kirk K. L.. Org. Proc. Res. Dev.[J], 2008, 12(2): 305—321 [14] O'Hagan D.. Chem. Soc. Rev.[J], 2008, 37(2): 308—319 [15] TAN Xian-Sheng(谭显胜), YUAN Zhe-Ming(袁哲明), ZHOU Tie-Jun(周铁军), WANG Chun-Juan(王春娟), XIONG Jie-Yi(熊洁仪). Chem. J. Chinese Universities(高等学校化学学报)[J], 2008, 29(1): 95—99 [16] Qiu X. L., Xu X. H., Qing F. L.. Tetrahedron[J], 2010, 66(4): 789—843 [17] FENG Qi(冯启), LIU Zhi-Li(刘智力), WANG Ming-Zhong(王明忠), YU Shu-Jing(于淑晶), LI Zheng-Ming(李正名). Chem. J. Chinese Universities(高等学校化学学报)[J], 2011, 32(1): 74—78 [18] Sleath P. R., Handlon A. L., Oppenheimer N. J.. J. Org. Chem.[J], 1991, 56(11): 3608—3613 [19] Larsen C. H., Ridgway B. H., Shaw J. T., Smith D. M., Woerpel K. A.. J. Am. Chem. Soc.[J], 2005, 127(31): 10879—10884 [20] Hertel L. W., Kroin J. S., Misner J. W., Tustin J. M.. J. Org. Chem.[J], 1988, 53(11): 2406—2409 [21] Mort C. J. W., Migaud M. E., Galione A., Potter B. V. L.. Bioorg. Med. Chem.[J], 2004, 12(2): 475—487 [22] Sorci L., Cimadamore F., Scotti S., Petrelli R., Cappellacci L., Franchetti P., Orsomando G., Magni G.. Biochemistry[J], 2007, 46(16): 4912—4922 [23] Munshi C. B., Fryxell K. B., Lee H. C.. Meth. Enzymol.[J], 1997, 280: 318—330 [24] Graeff R., Lee H. C.. Biochem. J.[J], 2002, 361(2): 379—384 [25] Cen Y., Sauve A. A.. J. Org. Chem.[J], 2009, 74(16): 5779—5789 [26] Yoshikawa M., Kato T., Takenishi T.. Tetrahedron Lett.[J], 1967, 8(50): 5065—5068 [27] Lee J., Churchil H., Choi W. B., Lynch J. E., Roberts F. E., Volante R. P., Reider P. J.. Chem. Commun.[J], 1999, (8): 729—730 [28] Mikhailopulo I. A., Pricota T. I., Timoshchuk V. A., Akhrem A. A.. Synthesis[J], 1981, (5): 387—390