Exploring the Role of Bromine at C(10) of (+)-4-[2-[4-(8-Chloro-3,10-dibromo- 6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11(R)-yl)-1-piperidinyl]-2- oxoethyl]-1-piperidinecarboxamide (Sch-66336):  The Discovery of Indolocycloheptapyridine Inhibitors of Farnesyl Protein Transferase

Abstract

The 10-bromobenzocycloheptapyridyl farnesyl transferase inhibitor (FTI) Sch-66336 (1) is currently under clinical evaluation for the treatment of human cancers. During structure-activity relationship development leading to 1, 10-bromobenzocycloheptapyridyl FTIs were found to be more potent than analogous compounds lacking the 10-Br substituent. This potency enhancement was believed to be due, in part, to an increase in conformational rigidity as the 10-bromo substituent could restrict the conformation of the appended C(11) piperidyl substituent in an axial orientation. A novel and potent class of FTIs, represented by indolocycloheptapyridine Sch-207758 [(+)-10a], have been designed based on this principle. Although structural and thermodynamic results suggest that entropy plays a crucial role in the increased potency observed with (+)-10a through conformational constraints and solvation effects, the results also indicate that the indolocycloheptapyridine moiety in (+)-10a provides increased hydrophobic interactions with the protein through the addition of the indole group. This report details the X-ray structure and the thermodynamic and pharmacokinetic profiles of (+)-10a, as well as the synthesis of indolocycloheptapyridine FTIs and their potencies in biochemical and biological assays.

Metalated Heterocycles and Their Applications in Synthetic Organic Chemistry

“…329 This kind of ipso-halogenation has been profusely used in indole transformations such as palladium-catalyzed couplings, due to the importance of this heterocyclic system in natural product chemistry. [330][331][332][333][334][335][336] In addition, the protodesilylation [337][338][339][340] or fluoride-promoted elimination 341,342 have also been employed on indoles and related systems as a way of removing an auxiliary silyl group, as shown in Scheme 66 for the synthesis of compound 245, which has been obtained via a palladium-catalyzed cyclization using the silylacetylene 244, being a precursor of a scaffold of psilocin. 343 Moreover, there are also examples of palladiumcatalyzed coupling reactions, such as the coupling of the 2-silylpyrrolopyridine 247 with allyl iodide to give the derivative 248 (Scheme 67).…”

“…470 Furan-derived organostannanes have been obtained mainly from the corresponding organolithiums as in the case of pyrroles (see above), their use being dedicated mainly to palladium-catalyzed Stille crosscoupling reactions. Thus, many examples of the use of furanylstannanes in palladium-catalyzed crosscoupling reactions have been reported in the last several years, generally using different halides as coupling counterparts 454e,471 as shown in the regioselective Stille coupling of 3,5-dibromo-2-pyrone (341) with 2-(tri-n-butylstannyl)furan (342) under copper cocatalysis, affording pyrone 343 (Scheme 92). 471r…”

“…Thus, mono- ipso -iodination at the most nucleophilic C-4 of bis(trimethylsilyl)pyrrole 242 to give the pyrrole 243 has been carried out using iodine and silver trifluoroacetate (Scheme ), in a formal total synthesis of the marine natural product lukianol A . This kind of ipso -halogenation has been profusely used in indole transformations such as palladium-catalyzed couplings, due to the importance of this heterocyclic system in natural product chemistry. − In addition, the protodesilylation − or fluoride-promoted elimination , have also been employed on indoles and related systems as a way of removing an auxiliary silyl group, as shown in Scheme for the synthesis of compound 245 , which has been obtained via a palladium-catalyzed cyclization using the silylacetylene 244 , being a precursor of a scaffold of psilocin ) …”

Mutations in the zebrafish hmgcs1 gene reveal a novel function for isoprenoids during red blood cell development

“…24,39,40 The specificity of lonafarnib has been previously described as a farnesyl protein transferase inhibitor. 41 For morpholino injections, antisense hmgcs1 morpholinos (AAT-CATATAACGGTGTTGGTTCGTG) were injected (0.025 mM) at the single-cell stage and fixed at the indicated time points within the figure legend. For all treatment groups (drug treatment and morpholino) statistical significance was obtained using a Fisher's exact test.…”

Mutations in the zebrafishhmgcs1gene reveal a novel function for isoprenoids during red blood cell development

“…Ro 48 8071 specificity for oxido-squalene synthesis has been previously described 24,24,38,39 . The specificity of lonafarnib has been previously described as a farnyesl protein transferase inhibitor 40 .…”