Synthesis of novel carbocyclic analogues of indolocarbazole natural products

Tetrahedron Letters

Volumn 40, Issue 20, 1999, Pages 3929-3932

  Riley, Dean A ^a   Simpkins, Nigel S ^a   Moffat, David ^b  

^a UNIVERSITY OF NOTTINGHAM   (United Kingdom)

^b UCB PHARMA   (Belgium)

Author keywords

[No Author keywords available]

Indexed keywords

CARBAZOLE DERIVATIVE; K 252A; PROTEIN KINASE C INHIBITOR; STAUROSPORINE;

ARTICLE; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME INHIBITION; REACTION ANALYSIS; STRUCTURE ACTIVITY RELATION; STRUCTURE ANALYSIS;

EID: 0033553502     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0040-4039(99)00572-9     Document Type: Article

References (18)

1. 1. (a) For an extensive survey of indolocarbazole alkaloids, see Gribble, G. W.; Bertbel, S. J. in Studies in Natural Products Chemistry, Vol 12, (Atta-ur-Rahman, Ed.) Elsevier Science 1993.
2. (b) For some recent medicinal chemistry studies, see Faul, M. M.; Winneroski, L. L.; Krumrich, C. A.; Sullivan, K. A.; Gillig, J. R.; Neel, D. A.; Rito, C. J.; Jirousek, M. R. J. Org. Chem. 1998, 63, 1961.
3. 2. Yamashita, Y.; Fujii, N.; Murkata, C; Ashizawa, T.; Okabe, M.; Nakano, H. Biochemistry 1992, 31, 12069.
4. 3. For details of the binding involved in kinase inhibition by Staurosporine, see (a) Lawrie, A. M.; Noble, M. E. M.; Tunnah, P.; Brown, N. R.; Johnson, L. N.; Endicott, J. A. Nature Struct. Biol. 1997, 4, 796.
5. (b) Prade, L.; Engh, R. A.; Girod, A.; Kinzel, V.; Huber, R; Bossemeyer, D. Structure 1997, 5, 1627.
6. (c) Toledo, L. M.; Lydon, N. B. Structure 1997, 5, 1551.
7. 4. Hong, H. Drug Discovery Today 1996, 1, 438.
8. 5. Ecker, G.; Chiba, P. Exp. Opin. Ther. Patents 1997, 7, 589.
9. 6. Wood, J. L.; Stoltz, B. M.; Dietrich, H-J.; Pflum, D. A.; Petsch, D. T. J. Am. Chem. Soc. 1997, 119, 9641.
10. 7. Link, J. T.; Raghavan, S.; Gallant, M.; Danishefsky, S. J.; Chou, T. C.; Bailas, L. M. J. Am. Chem. Soc. 1996, 118, 2825.
11. 8. Shankar, B. B.; Viet, A. Q.; Rizvi, R.; Kirkup, M. P.; McCombie, S. W.; Ganguly, A. K. Bioorganic Med. Chem. Lett. 1994, 4, 495.
12. 9. Faul, M. M.; Sullivan, K. A.; Winneroski, L. L. Synthesis 1995, 1541.
13. 2 requires C, 80.14; H, 4.42; N, 8.77%.
14. 11. Danishefsky, S. J.; Masters, J. J.; Young, W. B.; Link, J. T.; Snyder, L. B.; Magee, T. V.; Jung, D. K.; Isaacs, R. C. A.; Bornmann, W. G.; Alaimo, C. A.; Coburn, C. A.; Di Grandi, M. J. J. Am. Chem. Soc. 1996, 118, 2843.
15. 3) 3437, 2930, 2867, 1754, 1720, 1572 and 1462.
16. 13. Attempted hydrolysis under the conditions used by Faul (ref. 1b) was not successful.
17. 1H COSY experiments show this signal to be coupled to both the CHOH (δ 5.35) and to the proximal CHN (δ 6.05) signal, but not to any other signals. This arrangement is not compatible with the alternative regiochemical outcome for the ring expansion (see reference 6).
18. 50 of 9 nM for Staurosporine). Inhibitor activity was determined using PKC obtained from Sigma Chemical Company (Poole UK) and employing an assay system available from Amersham International PLC (Little Chalfont, UK). More detailed screening results will be disclosed elsewhere.