Design, Sythesis And Antitumor Activities Of Substituted Indole-3-Glyoxylate Derivatives

Cancer has become the most leading cause of death to human beings and severely threatened health and live of mankind. The chemotherapeutic medicines under clinical usage have drawbacks of low curative effect, high toxicity, difficult absorption, high price and are easy to induce multidrug resistance (MDR). It takes enormous efforts and spending worldwide every year to research and develop new medicines for preventing and treating cancer.Combined therapy is still the principal treatment to malignancy at present and chemotherapy is one of the main curing methods to cancer. The problem of increasingly severe MDR of tumor is the main reason to cause abortive chemotherapy. MDR directly relates with patients’ response to chemotherapy and their prognosis. NCI estimated that the more than 90% death of tumor patients concerned with MDR. Finding novel synthetic small molecule antitumor agents for overcoming MDR has currently become the focus of oncology.Microtubules, key components of the cytoskeleton, are composed ofα-tubulin andβ-tubulin heterodimers arranged in the form of slender hollow tubes. They are crucial in the development and maintenance of cell shape, in the transport of vesicles, mitochondria and other components throught cells, in cell signaling, and in cell division and mitosis. Tubulin inhibitor is one of major and important antitumor medicines. At present, most clinically used tubulin inhibitors at present come from nature directly or indirectly, such as Taxanes and Vincas. However, the use of these natural products has some puzzling disadvantages: rare resource, complex synthesis, lack of oral availability and easy to induce drug resistance. The expensive medical cost can not easily be afforded by ordinary patients.Indibulin is a novel synthetic small molecule anticancer agent with significant antitumor activity in vitro and in vivo. It destabilizes microtubules in tumor cells, as well as in cell-free system. This novel tubulin inhibitor was developed by ASTA Medica AG (DE). It has a number of superior properties: (a) curative treatment of Yoshida AH13 rat sarcomas at almost nontoxic doses; (b) oral applicability; (c) lack of neurotoxicity at curative doses; (d) efficacy toward MDR tumor cells; (e) easy to synthesis. Indibulin has been under clinical trials presently. In order to explore more potent antitumor agent, indibulin was selected as the leading compound for our new drug design and modification. On the base of literature report, the new substituted indole-3-glyoxylamides were designed by changing the substitution on indibulin’s indole ring and altering its aromatic heterocycle group at its nitrogen atom of its glyoxylmide group. 80 indibulin analogues were synthesized by two synthetic routes and their chemical structures were identified by ~1H-NMR and ESI-MS, and among them 70 compounds have not been reported in literature. All the synthesized indibulin analogues were tested cytotoxicity in vitro by the standard MTT assay against HeLa and SKOV3 cell lines. The result showed that 46 analogues were cytotoxic compounds and the IC50 values of 18 analogues were under 1μM. The cytotoxicity of 10 analogues was comparable to that of indibulin. Compound A-1 was selected to test in vivo antitumor activity and studied antitumor mechanism.A series of novel podophyllotoxin derivatives were designed using association strategy based on indibulin’s planar indole-3-glyoxyl structure and synthesized from podophyllotoxin. All the synthesized substituted indole-3-glyoxyl podophyllotoxins have not been reported in literature and their chemical structures were identified by ~1H-NMR, ESI-MS and HR-ESI-MS. All the synthesized podophyllotoxin derivatives were tested cytotoxicity in vitro by the standard MTT assay against HeLa and SKOV3 cell lines. The standard SRB assay was used to measure their in vitro cytotoxicity against K562 cell line and the adriamycin resistant K562 cell line (K562ADR). The result showed that all synthesized podophyllotoxin derivatives were cytotoxic compounds even against K562ADR cell line and the cytotoxicity of 4 analogues were comparable to that of indibulin or podophyllotoxin. Compound B-3 was selected to test in vivo antitumor activity and studied antitumor mechanism.The structure-activity relationships of the two series compounds were investigated according to the in vitro pharmacological results, which laid the foundation for further research.