Synthesis and Isolation of 5,6,7-Trimethoxy Indoles for Binding Diverse Functional Groups at the 3-Position of the Indole to Make Novel Combretastatin Derivatives

Teresa Rocha


Combretastatin A4 (CA4) is an effective chemotherapeutic (anticancer) drug that decreases cell proliferation and selectively kills tumors by deforming the tumor's vasculature, or the pathway through which they obtain nutrients, and thus starves the tumor cells. CA4 works by targeting and inhibiting the formation of tubulin, a key protein component in cell division and structure. CA4 has been used as a model for the production of many new drugs because of how effective it has proven to be against cancer cell lines. While CA4 is an effective chemotherapeutic drug, it is not the miracle cure the world needs thus necessitating the development of new drugs. Indoles are prominent in pharmaceuticals and are common throughout nature bonded at the 3-position (an example being the amino acid tryptophan) thus encouraging the utilization of indoles with substituents at the 3-position in new chemotherapeutic compounds. Synthesis of new potential drugs derived from CA4 has been extensively investigated but an indole substituted derivative bonded at the 3-position has yet to be studied in the present literature. Trimethoxy indole, due to its high cost, will be synthesized. This will be done thorugh the use of Hemetsberger-Knittel indole methodology in order to create an indole ester. The indole ester will then undergo saponification, subsequent decarboxylation and then will be halogenated at the 3-position. A coupling reaction will then be performed between the halogen substituted indole and an aromatic alkyne (3'-hydroxy-4'-methoxy phenylacetylene). The coupled product must then undergo selective hydrogenation in order to produce the desired indole CA4 derivative. Should this CA4 derivative exhibit good drug properties (as will be determined by an outside group), the outlined synthetic pathway will then provide potential for the generation of a new library of CA4 derivatives. This suggested pathway may also be applied to the functionalization of other chemotherapeutic drugs, such as chalcones and estrogen modulators which are being studied by fellow group members. Presently 5,6,7-trimethoxyindole-2-carboxylic acid has been made with 72% yield and its decarboxylation is being purused through the use of a well known procedure while other potential methods are being considered.


Cancer, Combretastatin A4, Indole

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