Structural features required for activity

A vast number of platinum compounds have now been screened for antitumor activity, and the results of these investigations have led to a set of empirical guidelines for the minimum structural features required for activity. Although they may be stated in various forms, the key structure-activity relationships... 

Recent studies on Asclepias curassavica [197], and Bersama abyssinica [198, 199] have shown that bufadienolides and cardenolides are cytotoxic and that hellebrigenin 3-acetate (XLIX) inhibits W 256 at 8 mg/kg. Structure-activity relationship studies on bufadienolides and cardenolides have failed to reveal the structural features required for activity [194]. 

The apparent necessity of a second signal for haustorial initiation provides another possibility for chemical control. Riopel and coworkers (2,12-14) observed a few years ago that gum tragacanth, a foliar extract, was a very potent haustorial initiator. Two active compounds were isolated (Xenognosin A shown below, and a flavonoid with similar structure). The structural features required for haustorial formation include a meta relationship of hydroxyl and methoxyl groups and an alkyl branching ortho to the methoxy substituent. 

Despite the small size of glycolipids, their complexity has still driven efforts for synthesis of simpler mimetics in an attempt to identify the minimal structural features required for the biological activity. To this end, many synthetic methods have been adopted in glycolipids synthesis, based on traditional glycosylation... 

Recently, Michalak et al. [156] presented a review on the interactions of phenothiazines with lipid bilayers and their role in MDR reversal. The drug partition between water and the lipid phase was discussed. The molecular size and polarizability of phenothiazines were found to correlate satisfactorily with the reduction of MDR. The most important structural features required for a high anti-MDR activity of phenothiazines seem to be their hydrophobic ring system, the type of substituent located at the 2-position, the presence of... 

Figure 7 Depiction of three macrocyclic carbonyl structures showing that only the ring of 15 atoms satisfies the requirement for musk order. A ring with more than 17 atoms or less than 13 atoms does not have the features required for activity.

The necessity to design compounds that would serve as therapeutic alternatives to acetylcholine and as probes to study the role of acetylcholine in neurotransmission led to an exhaustive study of the structural features required for the action of acetylcholine. Structure-activity relationships that developed from these studies have provided the basis for the design of all muscarinic agonists currently used as therapeutic agents. 

Hundreds of barbiturates have been synthesized on a trial-and-error basis. Although many structural features required for hypnotic activity have been recorded, no clear correlation between structure and activity has emerged. In 1951, Sandberg (43) made his fundamental postulation that to possess good hypnotic activity, a barbituric acid must be a weak acid and must have a lipid/water partition coefficient between certain limits. Therefore, only the 5,5,-disubstituted barbituric acids, the 5,5,-disubstituted thiobarbituric acids, and the 1,5,5-trisubstituted barbituric acids possess acceptable hypnotic, anticonvulsant, or anesthetic activity. All other substitution patterns, such as 5-monosubstituted barbituric acids, 1,3-disubstituted barbituric acids, or 1,3,5,5-tetrasubstituted barbituric acids, are inactive or produce convulsions. 

The development of SAR for endocannabinoid-derived structures has primarily focused on the anandamide skeleton (1) with a large number of publications addressing the requirements for activity and stability of this scaffold. More recently, some SAR has begun to emerge for the other end-ocannabinoids, in particular 2-AG (2). The following discussion will focus on highlighting some of the main features that contribute to affinity and/or stability each endocannabinoid will be treated separately. A number of detailed reviews on this subject have been published [142-146]. 

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