Oxindoles

Oxindole CDK inhibitors related to the pan-kinase inhibitor indirubin 56 isolated from Chinese herbal medicine [117,118] have been reported by several companies: Sugen (now Pfizer) [119,120] (57), Hoffman La Roche [121] (58), Boehringer Ingelheim [122] (59), and GlaxoSmithKline [123] (60). Many of these analogs were very potent inhibitors of the CDKs and exhibited excellent anti-proliferative activity against tumor cell lines. The series from GlaxoSmithKline [123] is selected here to exemplify this class of inhibitor and illustrate how, through the use of X-ray crystallography, modeling, and SAR studies, activity and selectivity were optimized.

Structure 56

57

Structure 57

The indolin-2-one template, a feature of inhibitors of the receptor tyrosine kinases of Her-2, VEGF, and EGF, was used by GlaxoSmithKline scientists as a starting point to design a series of analogs from which the selective CDK-2 inhibitor 60 (IC50 = 0.06 ^M) was identified. A thorough analysis of

58

Structure 58

Structure 59

Structure 60

the crystal structure of 60 complexed with the inactive form of CDK2 (Fig. 7) showed that the oxindole ring occupied the ATP binding pocket in a manner similar to previous compounds of this class: the oxindole NH donated a H-bond to the backbone carbonyl of Glu81 and the oxindole carbonyl oxygen of 60 accepted a H-bond from the backbone NH of Leu83. The 7-position of the oxindole was in close proximity to the Phe80 side chain and appeared to be too crowded to permit further substitution, while the 6-position projected toward a cavity in the back of the pocket into the region affected by cyclin A association. This cavity could accommodate only small substituents

Fig. 7 Compound 60 bound to CDK2

due to the bulk of the Phe80 side chain. The 5-position of the oxindole was close to Lys33, which suggested the possibility of a beneficial H-bond interaction at this location. A lipophilic substituent at the 4-position of the oxindole could result in a favorable interaction with the adjacent hydropho-bic environment. The sulfonamide group, which interacted with Asp86 at the opening of the binding cleft of CDK2, provided a site for substitution that would project into solution and could be used to adjust the physical properties of this series.

Disubstitution at the 4- and 5-positions provided potent inhibitors of CDK2. Especially effective were compounds with a fused heterocycle such as 61. The quinoline nitrogen was designed as a hydrogen bond acceptor to interact with the y-amino group of the Lys33 side chain. Compound 61, had excellent activity against CDK1 (IC50 = 0.00 1 5 ^M) and CDK2 (IC50 = 0.015 ^M). In the crystal structure of 60, the sulfonamide moiety formed two H-bonds, one with the backbone NH and one with the side-chain car-boxylate of Asp86 at the opening to the binding cleft of CDK2. However, the

h so2nh2

hi so2r

Structure 62

SAR demonstrated by sulfonamide 62a (CDK2 IC50 = 0.003 |M; CDK1IC50 = 0.029 |M) and sulfone 62b (CDK2 IC50 = 0.008 |M; CDK1 IC50 = 0.100 |M) suggested that the hydrogen bond between the sulfonamide NH and the Asp86 carboxylate did not play a significant role in binding. These compounds selectively inhibited proliferation of tumor cells over a human fibroblast "normal" cell line and arrested tumor cell proliferation at the G1/S phase check point, consistent with the CDK activity.

Chinese Herbs

Chinese Herbs

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