Acyl structure-activity relationship with

Previous syntheses An example of this point can be recognized by examination of one known synthesis of thienobenzazepines (Scheme 6.1). This synthetic route involves a key palladinm-catalyzed cross-conpling of stannyl intermediate 3, prepared by method of Gronowitz et al., with 2-nitrobenzyl bromide. Acetal deprotection and reductive cyclization afforded the desired thienobenzazepine tricycle 4. In support of structure activity relationship studies, this intermediate was conveniently acylated with varions acyl chlorides to yield several biologically active componnds of structure type 5. While this synthetic approach does access intermediate 4 in relatively few synthetic transformations for stractnre activity relationship studies, this route is seemingly nnattractive for preparative scale requiring stoichiometric amounts of potentially toxic metals that are generally difficult to remove and present costly purification problems at the end of the synthesis. 

The cholinesterases, acetylcholinesterase and butyrylcholinesterase, are serine hydrolase enzymes. The biological role of acetylcholinesterase (AChE, EC 3.1.1.7) is to hydrolyze the neurotransmitter acetylcholine (ACh) to acetate and choline (Scheme 6.1). This plays a role in impulse termination of transmissions at cholinergic synapses within the nervous system (Fig. 6.7) [12,13]. Butyrylcholinesterase (BChE, EC 3.1.1.8), on the other hand, has yet not been ascribed a function. It tolerates a large variety of esters and is more active with butyryl and propio-nyl choline than with acetyl choline [14]. Structure-activity relationship studies have shown that different steric restrictions in the acyl pockets of AChE and BChE cause the difference in their specificity with respect to the acyl moiety of the substrate [15]. AChE hydrolyzes ACh at a very high rate. The maximal rate for hydrolysis of ACh and its thio analog acetyl-thiocholine are around 10 M s , approaching the diffusion-controlled limit [16]. 

Structure-activity relationships can be inferred by comparison of the antibacterial properties of the clinical agents and related compounds. Different acyl side chains can result In significant changes in the antibacterial activity, both with respect to potency and to breadth of spectrum. The highest activities are observed when the aeylaniino side chain at C-7 is a substituted acetic add. Homologation of the acetic add moiety lowers activity dramatically as exemplified by1 the naturally occurring cephalosporins, which all have weak activity. 

In contrast to acetylcholinesterase, which is selective for acetylcholine, butyryl-cholinesterase tolerates a wider variety of esters and is more active with butyryl-and propionylcholines than acetylcholine [7]. Structure-activity relationship studies have shown that different steric restrictions in the acyl pockets of AChE and BChE cause the difference in specificity to the acyl moiety of the substrate [6]. 

Consequently, this cellular model was employed to evaluate the structure-activity relationship of some new acyl cyanides deduced from CMPC (Table 10.1). The derivatives with the highest biological activity compared to Leflunomide (A 77 1726) are shown with their respective ICjq values. Despite the fact that the activity increases slightly with chain length (CMPC < methyl-5-cyano-3-mefhyl-5-oxopentanoate < methyl-6-cyano-6-oxohexanoate), branching of the C-chain reduces the activity of methyl 5-cyano-3-mefhyl-5-oxopentanoate to less than 10% of CMPC. 

The modification of these natural polyhydroxylated compounds via acylation of the hydroxyl functions with aliphatic molecules not only increases their structural diversity, producing analogs that may be useful models for the study of structure-activity relationships, but also changes their physicochemical properties, increasing their solubility in lipophilic media. Moreover, the selective acylation of these natural compounds with various acyl donors could enhance their biological activities, such as their antioxidant and antimicrobial activity, as well as their pharmacological properties [5, 6]. 

Extensive early studies of in vitro and in vivo structure-activity relationships within the leucomycin family revealed correlations between the number and type of O-acyl substituents and the compounds antibacterial potency, efficacy in treating experimental infections, and serum antibiotic concentrations [26]. Consequently, esterification of all hydroxyl groups within several leucomycin-related macrolides was conducted to find derivatives with better antibiotic activity and pharmaceutical properties (such as greater water solubility and masking their extremely bitter taste). From such investigations with midecamycin, miokamycin was synthesized and characterized as a useful new macrolide antibiotic [24, 27]. It has now been commercially launched in several countries [5]. 

Ginsenoside Ro (Fig.(l)) has been screened for activity in experimental models of inflammation. This saponin (10, 50, 200 mg/kg, p.o.) inhibited an increase in vascular permeability induced by acetic acid in mice and reduced an acute paw oedema in rats induced by carrageenin [88], Similar results were obtained in these experiments with pure escins la, lb, Ila, lib (50-200 mg/kg) (57-57c) from Aesculus hyppocastanum [88a]. According to structure-activity relationship studies, the acyl groups were essential in the escins. 

To study the structure-activity relationships of the fatty acyl side chains, it was desirable to have a method to remove the natural fatty acids from the A21978C complex of antibiotics. The fatty acid side chains could not be removed chemically without significant destruction to the peptide core. However, the side chains were readily removed by incubation of the complex with a culture of A. utoKemis (2,3). Enzymatic deacylation resulted in complete loss in antibacterial activity (2). Deacylation also occurred with A2I978C... 

At this point we decided that it would be useful to develop a structure-activity-relationship around a series of hindered phenylalanines to determine whether we had the best substitution for activity. We followed a three-pronged attack (Figure 1), A) substitution of the methyl in the mercaptomethyl with other groups, B) substitute the phenyl with additional groups or replace the 2-methyl with other atoms or groups and C) Use different acyl groups odier dian the methoxyacetyl. 

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