Drug research structure modification

The structural modification of natural products is useful in several ways. The known pharmacology of bisindole alkaloids is enriched by the diversity of chemical structures that are made available by structure modification and total synthesis. These molecules have served as biochemical probes in several areas of biology, especially in those of microtubule assembly and drug resistance. The most elusive prize, however, has remained the discovery of new compounds with clinical activity. In recent years several compounds have been evaluated in clinical trials, but vinblastine and vincristine remain the only bisindole alkaloids approved for the treatment of cancer in the United States. These compounds are joined by vindesine in Europe, and at least two new derivatives are the subject of ongoing clinical trials. Considering the breadth of chemical research in this area, the overall yield as measured by new compounds with clinical activity has been relatively low, but this observation is not unique in history of analog development in cancer research. Nevertheless, the search continues, and this chapter details the chemical endeavors to discover a new bisindole alkaloid with clinical activity. 

The structural and biological diversity of the cyclic lipopeptide antibiotics is extremely attractive to chemical, pharmacological and medical sciences. Future rational drug design, chemical modification and discovery of novel cyclic lipopeptides from natural sources will give rise to useful biological tools for research and development in the medicinal sciences. 

The rapid structure identification of metabolites provides an early perspective on the metabolically labile sites or soft spots of a drug candidate [86], This information is useful during lead optimization and can serve to initiate research efforts that deal with metabolism-guided structural modification and toxicity. 

From the point of view of importance and chemical feasibility, chloramphenicol (Figure 9) presented an excellent subject for structural modification. It was the first truly broad-spectrum antibiotic isolated, and its structure and total synthesis were both reported two years after the discovery was announced (40, 41, 42). The synthesis of chloramphenicol analogs proved to be one of the great disappointments of early chemical research in the antibiotic field. Hundreds of analogs were synthesized, but none was found superior to the parent drug in terms either of antimicrobial activity or therapeutic index (43). The palmitate and hemisuccinate esters have provided superior dosage forms for oral and parenteral use. One synthetic analog, thiamphenicol (44) has achieved limited use in human and veterinary medicine. 

Ethnopharmacological research on natural products can contribute to the discovery of new active compounds with novel structures which may serve as leads to the development of new antiepileptic drugs. An example is the isolation of the active alkaloid piperine from Piper nigrum L. which is one of the component herbs of an ancient Chinese medicine used for the treatment of epilepsy. Its structural modifications resulted in the synthesis of seven derivatives including antiepilepserine which was found to be more potent than the parent compound with fewer side effects and it has been used as an antiepileptic drug [10-12]. 

Natural Products Chemistry has contributed significantly towards the development of modem medicines. Many of the modem medicines are modifications or survivals of ancient herbalism. Natural products often serve as chemical models for the design and total synthesis of new drugs.The structure elucidation of natural products which was once an attractive area of research is no longer the spearhead of the subject. The application of the powerful spectroscopic techniques has tremendously... 

In contrast to the SOSA approach, many of the hits obtained from HTS do not have a drug-like structure and it may require far more effort to optimize them. Indeed, it has been argued that modifications of known drug structures should provide lead compounds in several areas of medicinal chemistry [36]. Many research groups are now screening compounds that are either in clinical use or have reached late-stage clinical trials to see whether they have side activities that would make them suitable lead compounds. 

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