Drugs patterned synthesis

Patterned synthesis is also an active line (Table 15. III), best illustrated by ephedrine, which served as a model for many synthetic CNS-active drugs (Table 15.III). Patterned synthesis is aimed at... 

At the borderline between semisynthesis and patterned synthesis, versatile total syntheses may provide access to diversified bioactive structures. Classically, analogues of the active drug are sought that avoid the resistance developed by pathogens and show reduced side effects. In lucky cases, chemical simplification has afforded the wonder drug. This is the case of sodium valproate (2-propylvaleric acid sodium salt), which was synthesized in the fall of the XIX century and nearly a hundred years later became a leading drug in the treatment of epilepsy. 

The latter type of compounds should preferably carry either one type I unit or at most two units (positioned as far apart as possible), and have an elongated structure (which does not fold as verapamil, for example) with a small cross-sectional area, Ad- The first type of compounds is expected to be transported slowly, whereas the second type may not be transported. Table 20.2 summarizes the drug properties relevant for transporter binding and lipid partitioning of a substrate (modulator or inhibitor) of P-gp. Inspection of the information contained in Table 20.2 shows that the synthesis and membrane incorporation of inhibitors with a low number of H-bond acceptor patterns should be simpler and more efficient than that of inhibitors with a large number of patterns. 

Since the main clinical use for antisympathotonics is in the treatment of essential hypertension, such drugs will be discussed in Chapter 20 in more detail. The alkaloid reserpine from Rauwolfia serpentina was the first drug used clinically to reduce sympathetic tone. Reserpine reduce the ability of storage and release of various transmitters (adrenaline, noradrenaline, serotonine and dopamine) by an irreversible destruction of the axonal vesicle membranes. The duration of the reserpine effect is actually determined by the de novo synthesis of these structure. Beside various central side effects like sedation, depression, lassitude and nightmares the pattern of unwanted effects of reserpine is determined by the shift of the autonomic balance towards the parasympathetic branch myosis, congested nostrils, an altered saliva production, increased gastric acid production, bardycardia and diarrhea. As a consequence of the inhibition of central dopamine release, reserpine infrequently shows Parkinson-like disturbances of the extrapyramidal system. 

A list of drugs of abuse is provided in T able 13.6. Numerically it is dominated by the alkaloids and products of synthesis patterned on alkaloids, like the amphetamines and Ecstasy. Meroterpenes have... 

Table 15.III. Drugs and technologically relevant agents from synthesis patterned on natural...

The study of various anticancer drugs shows that many possess an optimal circadian delivery pattern, according to the phase of the cell cycle in which the cytotoxic effect is exerted. A case in point is provided by 5-FU. This widely used anticancer drug interferes with DNA synthesis and acts during DNA replication, the S phase of the cell cycle. Cells exposed to 5-FU during the S phase have an enhanced proba-... 

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