Nh

c, d

Scheme 5. Modifications of BPHI at positions 1 or 3, synthesis of compounds II/57-58. (a) 2-(phe-nylsulfonyl)-3-phenyloxaziridine / CHCl3 (rt). (b) PhLi / THF (0° to rfx.). (c) H2 / Pd-C / MeOH. (d) (o.methoxyphenyl)acetic acid / EDCI / HOBT / CH2Cl2.

Me02C

Scheme 5. Modifications of BPHI at positions 1 or 3, synthesis of compounds II/57-58. (a) 2-(phe-nylsulfonyl)-3-phenyloxaziridine / CHCl3 (rt). (b) PhLi / THF (0° to rfx.). (c) H2 / Pd-C / MeOH. (d) (o.methoxyphenyl)acetic acid / EDCI / HOBT / CH2Cl2.

4.3. Modifications at Positions 1 and 3 on the Pyrrolidine Ring (Scheme 5)

The oxidation ofmethyl 2H-4,9-ethano-9-phenyl-2,3,3a,4,9,9a-hexahydro-1H-benzo [f]isoindole-3a-carboxylate by 2-(phenylsulfonyl)-3-phenyloxaziridine (46), followed by easy chromatographic separation ofthe resulting nitrones and by subsequent reaction ofphenyllithium (or alkyllithium reagents) on the less hindered face ofthe molecule, led to the preparation of BPHI stereoselectively substituted at positions 1 and 3 by alkyl or aryl groups such as phenyl derivatives II/57-58. (Scheme 5).

4.4. Chiral Resolution of BPHI

When needed for further biological evaluations, enantiomers of active BPHI were easily obtained through chiral HPLC resolution on silica-gel bearing (2,3-dinitrobenzoyl)-S-phenylalanine residues as chiral resolving agents (47,48).

More than 400 compounds have been synthesized in the BPHI series. The strategy used to evaluate the FTase inhibition is primarily based on their potency both to inhibit the farnesylation ofRas proteins or related peptides by human FTase and to prevent Ras-processing in intact cells. For historical reasons, owing to the availability ofRas protein, the first 200 compounds have been evaluated using Ha-Ras as protein substrate. We then evaluated the ability ofinhibitors to prevent the farnesylation ofa Ki-Ras relatedpeptide, which is more relevant to the clinical situation. Usually BPHI inhibit the farnesylation of both substrates with near or equal potencies.

The FTase inhibitory potency of (±) II/1 (IC50 = 0.2-0.31 ^M) in SPA/lamin B assay was confirmed in a TCA/ Ha-Ras assay (IC50 = 0.31 ^.M) as well as a SPA/Ki-Ras assay (IC50 = 0.2-0.3 ^M). This lack of protein substrate selectivity is a general feature within

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