Structure activity analogues

Structure—Activity Relationships. In spite of the considerable synthetic and bioassay effort involved in estabhshing the thyromimetic potency of thyroid-hormone analogues, more than 100 compounds have been studied (Table 2). The main stmctural requirements for thyromimetic activity can be summarized as follows (6,12—16). 

Coleman et al. have performed a preliminary structure/activity study for a series of analogues of 77 [149]. They found that removal of the naphthoate moiety (88 Scheme 11.11) dramatically reduced the yield of DNA alkylation, while replacement of the NH2 group with O-benzyl (89 and 90) abolished DNA alkylation completely. Compound 91 alkylated DNA with reduced efficiency, so this effect is not simply due to a requirement for a hydrogen bond donor at this position. Perhaps the amide is required at this position to increase the ability of the C=0 to act as a hydrogen bond acceptor. Importantly, they found a strong correlation between the extent of in vitro DNA alkylation and cell culture cytotoxicity. 

Very recently, the Shipman group have made a further step towards a comprehensive structure/activity profile for noncovalent interactions between azinomycin B and DNA [152]. They synthesized simplified azinomycin analogues 69 and 96-98 (Scheme 11.13), retaining both the epoxide and aziridine alkylating functionalities, with systematically altered substitution on the naphthoate fragment, and analyzed their DNA crosslinking by gel electrophoresis. They found that cross-... 

The structure activity relationships ( SAR) of newly synthesized analogues of nucleosides, xanthine heterocycles, and nonxanthine heterocycles have been explored at the ARs. Potent and selective AR antagonists have been prepared for all four subtypes [3, 4], and selective agonists are known for three subtypes [1]. Thus, numerous pharmacological tools are available for in vitro and in vivo use (Table 2). Potent and selective A2b AR agonists are yet to be repotted, although several research groups have identified lead compounds. 

Synthesis and structure-activity data of some new epibatidine analogues [70]... 

Medvedev AE, Veselovsky AV, Shvedov VI, Tikhonova OV, Moskvitina TA, Fedotova OA, et al. Inhibition of monoamine oxidase by pirlindole analogues 3D-QSAR and CoMFA analysis. / Chem Inf Comput Sci 1998 38 1137-44. Miller JR, Edmondson DE. Structure-activity relationships in the oxidation of para-substituted benzylamine analogues by recombinant human liver monoamine oxidase A. Biochemistry 1999 38 13670-83. 

In 1985, it was reported by Hsiang et al. [43] that the cytotoxic activity of 20-(S)-camptothecin (CPT III) was attributed to a novel mechanism of action involving the nuclear enzyme topo I, and this discovery of unique mechanism of action revived the interest in CPT and its analogues as anticancer agents. CPT stabilizes the covalent, reversible topo I-DNA complex leading to the inhibition of DNA synthesis in mammalian cells and interferes with the topo I breakage-reunion reaction [44]. Clinical trials and structure-activity relationships have demonstrated the requirement of the a-hydroxy group, the... 

Another interesting finding was that two structurally close analogues of (15a), namely compounds (15b) and (15c), showed marked species-related differences in activity they behaved as weak antagonists towards hTRPVl, and weak agonists towards rTRPVl [78]. This observation indicates that great caution should be taken when extrapolating TRPVl actions from animal models to humans ... 

The structure-activity relation of triterpene QMs on the anti-inflammatory effect has been investigated with a series of analogues by comparing inhibition of the IL-1 (3 production in the LPS-induced monocytes.93-94 Clearly, the conjugated QM structure with alkenes is essential for the observed inhibition, and similar inhibitory effect was found with derivatives that are capable to form the conjugated QM through hydrolysis and/or oxidation.93-94 Also, the presence of the E ring in the triterpene QM structure is an additional contributor. 

Ha JH, Shin SM, Lee SK, et al. In vitro effects of hydroxybenzaldehydes from Gastro-dia elata and their analogues on GABAergic neurotransmission, and a structure -activity correlation. Planta Med 2001 67 877-880. 

Hellberg, S., Eriksson, L., Jonsson, J., Lindgren, F., Sjostrom, M., Skagerberg, B., Wold, S. and Andrews, P. (1991), Minimum analogue peptide sets (MAPS) for quantitative structure-activity relationships , Int.J. Peptide Protein Res., 37, 414-424. 

The range of these aza-ellipticine analogues, although by now extensive, is still insufficient to permit a systematic evaluation of their structure-activity relationships. It is established, however, that the three methylated compounds 11-13 are all less active than ellipticine toward a range of tumor cell lines <2004AP434>. 

Meyers MJ, Sun J, Carlson KE, Marriner A, Katznellenbogen BS, Katzenellenbogen JA (2001) Estrogen receptor-/ potency-selective ligands structure-activity relationship studies of diarylpropionitriles and their acetylene and polar analogues. J Med Chem 44 4230-4251... 

Haefliger, W., Revesz, L., Maurer, R., Romer, D., and Buscher, H.-H. (1984) Analgesic GABA agonists. Synthesis and structure-activity studies on analogues and derivatives of muscimol and THIP. Eur. J. Med. Chem. 19,149-156. 

Synthesis, cytotoxicity in vitro and in vivo, and structure-activity relationships of septicine 280 and its analogues were reported (Figure 7) <2003BML1679>. 

Also 2-alkylpyridazinones of type (4, R1, R2 = alkyl) [26, 27] and type (5, R1, R2 = alkyl) [28, 29], being regioisomers of compounds (2), as well as thio-analogues (6, R1, R2 = alkyl) [30] and 2-alkenyl congeners [31], have been reported in the patent literature to exhibit such activities. Structure-activity... 

The most potent among the compounds tested were the pyridazi-nones (28, R1 = Ph, R2, R3, R4, R5 = H, n = 2-5) [101]. Structure-activity relationships have been investigated in detail with this type of compound. Also, thio-analogues of compounds (28) (3-pyridazinethione derivatives) as well as 2-aminoalky]-6-aryl-3(2//)-pyridazinones were claimed in patents as gastric secretion inhibitors or anti-ulcer agents [100, 102, 103]. 

Structure-activity studies are probably adequate for some substances. An example would be inert polymers whose monomeric components have been well-characterized toxicologically. For other chemicals, analyses based on a review of structural analogues may prove inadequate for at least three reasons. 

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