Synthetic analogues

Unlike aromatic rings, double bonds are easy to reduce and this has a significant effect on the shape of that part of the molecule. The planar double bond is converted into a bulky alkyl group. 

If the original alkene was involved in van der Waals bonding with a flat surface on the receptor, reduction should weaken that interaction, since the bulkier product is less able to approach the receptor surface (Fig. 7.10). 

Once it is established which groups are important for a drug s activity, the medicinal chemist can move on to the next stage—the synthesis of analogues which still contain these essential features. 

Drug development in the past has mostly been a hit or a miss affair with a large number of compounds being synthesized at random. Luck has played a great part, but we can now recognize strategies which have evolved over the years  

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Table 2. Synthetic Analogues of Oxytocin with High Potency or Selectivity...

Table 4. Synthetic Analogues of Oxytocin and Vasopressin Having Antagonist Activities...

The use of SPPS allows synthesis of both native oligopeptides and important synthetic analogues. Many of these fragments or substituted analogues have been found to be equal to, or more potent than, the parent molecule and to exhibit long-acting and antagonistic activities. 

Enterobactin (ent), the cycHc triester of 2,3-dihydroxy-A/-benzoyl-l-serine, uses three catecholate dianions to coordinate iron. The iron(III)-enterobactin complex [62280-34-6] has extraordinary thermodynamic stabiUty. For Fe " +ent , the estimated formal stabiUty constant is 10 and the reduction potential is approximately —750 mV at pH 7 (23). Several catecholate-containing synthetic analogues of enterobactin have been investigated and found to have lesser, but still impressively large, formation constants. 

One technology uses bovine somatotropin (bST) produced by recombinant technology (38). Somatotropin [9002-72-6] is a growth hormone. The bST-supplemented cows provide an increase in milk output per cow or an increased feed efficiency. Recombinant bST, also known as recombinant bovine growth hormone (rBGH) is the synthetic analogue of a natural hormone that increases milk production in cows (39). The use of recombinant technology was approved by the FDA in 1993. The Commission of the European Community has recommended that the moratorium on commercial use of BGH be delayed until the year 2000. 

Muramyl tripeptide phosphatidylethanolamine (MTP-PE), a synthetic analogue of muramyl dipeptide and an effective systemic macrophage activator, induces a variety of cytokines such as IL-1, IL-6, and TNE, as well as PGE2 (205). Preirradiation treatment of mice using MTP-PE encapsulated in Hposomes, which can intensify radioprotective abiHty, stimulates the monocyte/macrophage system and accelerates the recovery of hemopoietic cells. 

The natural compounds cortisol [50-23-7], cortisone [53-06-5], and corticosterone [50-22-6] vary only slightly in stmctures and pharmacologic properties (see Steroids). The synthetic analogues inmore modem practice, prednisolone [52438-85-4], dexamethasone [50-02-2], triamcinolone [124-94-7], and betamethasone have greater antiinflammatory potency, and their effects on sodium retention tend to be less severe. 

A.n log ue Synthesis. Two notable examples, in which analogues have greater therapeutic indexes than the parent dmgs, have been identified in Phase I trials. These are carboplatin (29) and ado2elesin (37) (35). Carboplatin s approval was based on its comparable efficacy to cis-platinum (28) and its more favorable toxicity profile, ie, reduced and delayed episodes of emesis, reduced ototoxicity, etc. On the other hand, ado2elesin, a totally synthetic analogue of natural product CC1065, has demonstrated a similar potency and antitumor activity profile as its natural prototype but is devoid of the delayed death UabiUty associated with the parent dmg in animals (36). 

While the natural monobactams do not appear to have clinically useful activity, a number of their totally synthetic analogue.s do. This field has been explored intensively in recent years and some of the fruits of this work are reported here. 

The core cavity of the aequorin molecule can accommodate various synthetic analogues of coelenterazine in place of coelenterazine. The replacement of the coelenterazine moiety of aequorin can be... 

Lombardi, P. and A. Crisanti. Antima-larial activity of synthetic analogues of distamycin. Pharmacol. Then 1997, 76, 125-133. 

Despite the clear loss of somatostatin in AzD a synthetic analogue L-363586 had no beneficial effect on memory loss. 

Laursen, J.B and Nielsen, J., Phenazine natural products biosynthesis, synthetic analogues, and biological activity, Chem. Rev., 104, 1663, 2004. 

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