Structure-activity profiling

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-... 

Owing to a curious overlap of interest in different laboratories, this class of vanilloid antagonists is better investigated than others with regards to both structure-activity relationships and in vivo profile of activities. 

Among the possible alternative methods, in vitro assay (for ATMs) and quantitative structure-activity relationships (QSARs) models (for ANTMs) are the most applied approaches in the toxicological and ecotoxicological evaluation of chemicals profiles, even in the field of environmental research and risk assessment. 

From the examination of structure-activity relationships, it has been concluded that a phenyl moiety at C-6 as well as a 4-hydroxypiperidine side-chain attached to C-3 of the pyridazine system is essential for anticonvulsant activity in this class of compounds [184], Compounds (54) and (55) have been found to have similar anticonvulsant profiles in animals (mice, rats and baboons) [165, and literature cited therein] and to represent potent broad-spectrum antiepileptic drugs. Their potency with regard to antagonizing seizures (induced by electro-shock or various chemicals) has been compared with standard anticonvulsants like carbamazepine and phenobarbitone [185, 186], A quantitative electroencephalographic analysis of (55) has been published [187]. From in vitro studies it has been concluded that the anticonvulsant activities of these compounds are not mediated by an enhancement of GABAergic transmission or by an interaction with benzodiazepine receptor sites [ 165,186,187], On the other hand, in vivo experiments showed that (54), at anticonvulsant doses, increases the affinity of flunitrazepam for its central receptor site [ 186], Investigations of (54) and (55) in a behavioural test predictive of antianxiety activity revealed a marked difference in the pharmacological profiles of these structurally closely related compounds the dichloro compound SR 41378 (55) has also been found to possess anxiolytic (anticonflict) properties [165],... 

The early empirical structure-activity relationships promoted discovery of second-generation anticancer drugs such as complexes 2 and 3. However, analogs of these drugs usually display similar clinical profiles to the parent drugs. Therefore new classes of platinum complexes are required with distinct properties. 

Nelson, D.L. (1991) Structure-activity relationships at 5-HT1A receptors binding profiles and intrinsic activity. Pharmacology, Biochemistry, and Behavior, 40, 1041-1051. 

C-atoms (19,20). These compounds showed a typical structure-activity correlation between the length of the alkyl side chain and their antitumor activity profile (19). The pharmacokinetic, cytotoxic, and pharmacological properties of N -hexadecyl-ara-C were intensively examined, followed by several studies on the most effective derivative, N -octadecyl-ara-C (NOAC), which is highly... 

Tab. 9.2 Target class profile for WOM BAT.2004.1. Numbers in the Compounds column indicate the number of structures active at least once per each target, and the percentage from the total number of entries is given in the rightmost column...

Shimazaki, Y., Sugarawa, Y, Manabe, T. Nondenaturing two-dimensional electrophoresis enzyme profile involving activity and sequence structure of cytosol proteins from mouse liver. Proteomics 2004, 4, 1406-1411. 

Thus, a synthetic source of promising allelochemicals is essential if we are to comprehensively study the agent s mode of activity and establish its basic structure-activity profile. The proposed work addresses this need. We will synthesize alleopathic natural products isolated from the sunflower (the heliannuols), and structurally related compounds, in optically pure form based on biomimetic phenol-epoxide cyclizations. The bioactivity of the targets and intermediates will be evaluated through laboratory tests on plant germination and growth. Bioassays will be performed on the synthetic intermediates to allow for the development of a preliminary structure-activity profile for these novel natural herbicides. 

We also plan to perform bioassays on synthetic intermediates and target compounds to allow for development of a preliminary structure-activity profile for these novel herbicides. 

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