Constrained analogues

Thomas and co-workers [277] reported that irradiation of (382) with a 450 W high-pressure mercury lamp brought about photocyclisation to a constrained analogue (394). The structure of the product was elucidated through NMR and X-ray diffraction analysis. The compound retained high affinity for the CBi receptor (Xj = 48 nM) and good selectivity over the CB2 receptor (K[ — 3,340 nM). 

Kline and co-workers describe the preparation and biological evaluation of constrained analogues of 30,C12-HSL, the longer chain AHL produced by P. aeruginosa. Their compounds 20-23 differ from the previous studies as these were designed to have a rigid functional group in order to probe the bioactive tautomer of the 3-oxo amide functionality [66]. 

Castellano, S., Kuck, D., Sala, M., Novelhno, E., Lyko, F. and Sbardella, G. (2008) Constrained analogues of procaine as novel small molecule inhibitors of DNA methyltransferase-1. Journal of Medicinal Chemistry, 51, 2321—2325. 

Evidence for this conformation was provided by NMR and X-ray, but finally by synthesis of constrained analogues, including 43 which incorporates a y-lactam /3-turn mimic developed by Freidinger et al. (1989). Compound 43 was found to be 10 000 times more potent than 42 in enhancing the binding of the agonist 2-amino-6,7-dihydroxy-l,2,3,4-tctrahydronaphthalene. 

As a topographically constrained analogue of tyrosine, p,2,6-trimethyltyrosine (TMT) offers many advantages for topographical design of peptide and peptidomimetic analogues due to its very well-defined conformational and dynamic properties. Examination of the yflyf en-... 

It has been confirmed that conformationally constrained molecules have a greater effect on biological properties when compared to the relatively flexible open-chain compounds in many cases (e.g., see [75-82] for a few examples, see [83-92]). For example, UAB-8, a conformationally constrained analogue of... 

On the basis of these experiments, we anticipated that conformationally constrained analogues of our open chain diamides (1 and 2) may increase activity against cancer cell lines. In (3-lactam chemistry, this kind of hypothesis had been tested, and it was established that certain (3-lactams are more effective at lowering cholesterol in human plasma when compared to open-chain substrates [12-15]. Therefore, preparation of (3-lactams of type 3 and related compounds was necessary to investigate a comparative study with diamides 1 and 2. 

Ring-constrained analogues 37 of the anti-inflammatory drug, diclofenac, have been prepared by acid-catalyzed condensation of aldehydes (or ethylene ketals of ketones) with 36 (Equation 4) <1998MI201>. This reaction presumably proceeds via intramolecular nucleophilic attack by the carboxylic acid group on an iminium ion intermediate from condensation of the secondary amine. Interestingly, the compounds 37 showed comparable activities to diclofenac in the formalin-induced rat paw edema test. 

An interesting comparison can be made looking at the a- and (5-tetralin derivatives entries—15/16 and —17 in Table 1 which can be regarded as cyclic confor-mationally constrained analogues of phenylglycine and phenylalanine. In an interesting study, 6-hydroxy-2-aminotetralin-2-carboxylic acid 12 (Hat) has been incorporated as a conformationally constrained tyrosine analogue into S-opioid receptor selective tetrapeptides.114 15 Whereas entry 15, the (S)-a-tetralin deriva-... 

TABLE 1 Binding Affinities and In Vitro Bioactivities of Tyr1 Topographically Constrained Analogues of DPDPE in x Space... 

Mosberg and co-workers utilized a similar type of approach for constraining the flexibility of Tyr in JOM-13 [69]. In an effort to better determine the binding conformation of the Tyr1 residue, a series of conformationally constrained analogues of Tyr (FlO-Tic 7-hydroxy-1,2,3,4-tetrahydroisoquin-oline-3- carboxylic acid Flai 6-hydroxy-2-aminoindan-2-carboxylic acid Hat 6-hydroxy-2-aminotetralin-2-carboxylic acid, and c-Hpp and t-Hpp ... 

Tab. S.1 (f, app values versus human cathepsin K for acyclic and constrained analogues [19].

Ganesh, T. Guza, R. C. Bane, S. Ravindra, R. Shanker, N. Lakdawala, A. S. Snyder, J. R Kingston, D. G. I. The bioactive taxol conformation of P-tuhulin experimental evidence from highly active constrained analogues. Proc. Natl. Acad. Sci. USA, 2004, 101 10006-10011. 

Hardegger, E., and Ott, H. 1955. Konfiguration des cocains und derivate der ecgoninsaure. Helv ChimActa 38, 312-320. Hernandez, A., and Rapoport, H. 1994. Conformationally constrained analogues of anatoxin, chirospecific synthesis of s-trans carbonyl ring-fused analogues. J Org Chem 59, 1058-1066. 

The SAR of the constrained analogues together with the information obtained from biophysical smdies (X-ray, NMR) and computational methods can be used, in an... 

A new synthesis of enantiomerically pure 2-amino-3-phenyl-l-cyclopropane-phosphonic acid, a constrained analogue of phaclofen (267), has been described. The sulfoxide (268) of (S) configuration was found to undergo cyclopropanation... 

---