Synthesis of isomeric 3-piperidinyl and 3-pyrrolidinyl benzo[5,6]cyclohepta[1,2-b]pyridines: Sulfonamido derivatives as inhibitors of Ras prenylation

Bioorganic and Medicinal Chemistry

Volumn 6, Issue 6, 1998, Pages 673-686

  Kelly, Joseph ^a   Wolin, Ronald ^a   Connolly, Michael ^a   Afonso, Adriano ^a   James, Linda ^a   Kirshmeier, Paul ^a   Bishop, W Robert ^a   McPhail, Andrew T ^b  

^a MERCK RESEARCH LABORATORIES   (United States)

^b DUKE UNIVERSITY   (United States)

Author keywords

Dual FPT GGPT inhibitors; Farnesyl protein transferase inhibitors; FPT Inhibitors; Inhibitors of Ras prenylation; Sulfonamido tricycles as FPT inhibitors

Indexed keywords

ANTINEOPLASTIC AGENT; PIPERIDINE DERIVATIVE; PROTEIN FARNESYLTRANSFERASE INHIBITOR; PYRROLIDINE DERIVATIVE; RAS PROTEIN; SULFONAMIDE;

ARTICLE; DRUG SYNTHESIS; ENZYME INHIBITION; PRENYLATION; STRUCTURE ACTIVITY RELATION;

ALKYL AND ARYL TRANSFERASES; ENZYME INHIBITORS; PIPERIDINES; PROTEIN ISOPRENYLATION; PROTO-ONCOGENE PROTEINS P21(RAS); PYRIDINES; PYRROLIDINES; STRUCTURE-ACTIVITY RELATIONSHIP; SULFONAMIDES;

EID: 0031804891     PISSN: 09680896     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0968-0896(98)00026-1     Document Type: Article

References (40)

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34. The terms 4-piperidino, 3-piperidino and 3-pyrrolidino are used for convenience to denote the carbon of the pendant piperidine or pyrrolidine ring that forms the olefinic bond at C-11 of the benzocycloheptapyridine tricycle.
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37. (a) The olefinic geometries were established by NMR studies wherein an NOE effect in the Z-isomers 3b was observed between the C-10 proton and the allylic protons on the lactam ring.
38. (b) X-Ray crystallographic data on 6b and 56 is available from the authors.
39. The mixed sulfonic anhydride 14 obtained by reacting 3-pyridinesulfonic acid with p-nitrobenzenesulfonyl chloride (Scheme 2) was used to preparare the 3-pyridylsulfonamides 36 and 59. 20. The chemical shifts of the allylamino protons in the sulfonamido derivatives of Z-compounds II are deshielded by 0.2-0.3 ppm relative to the corresponding derivatives of the E-compounds III.
40. FPT and GGPT assays were performed over a wide range of inhibitor concentrations in half-log increments. Each data point was typically generated by duplicate determinations and the mean value was used to calculate percent inhibition relative to a vehicle (DMSO) control. Duplicates were within ± 5% of the mean value.