Design, synthesis and biological evaluation of novel serotonin reuptake inhibitors and novel derivatives of a nitrogen-containing combretastatin analog.

Includes bibliographical references (p. 402-414).Depression is a common and serious illness that affects one out of every ten Americans each year. Since the 1980's, selective serotonin reuptake inhibitors (SSRIs) have been the pharmaceuticals of choice for the treatment of depression and related disorders. Despite their indisputable efficacy, there is still room for improvement in SSRIs, especially in regard to their onset of action and adverse reaction profile. The research presented herein focused on the design and synthesis of a library of thirty-three novel bivalent molecules that could combine into one molecular entity an enhanced antagonism towards the 5-HT2A receptors while keeping a highly selective inhibition of the serotonin transporter (SERT). These bivalent molecules were constructed by covalently coupling two types of fluoxetine hydrochloride structural homologues (for SERT affinity) with a series of nine functionalized piperazines and piperidines (for 5-HT2A antagonism). Preliminary biological evaluation shows that two of the synthesized molecules, 16b and 17b, exhibit the desired dual activity (Ki = 237 and 195 nM respectively for the 5-HT2A receptor and Ki = 1.2 and 1.8 microM respectively for SERT). The complete set of biological data will outline the potential of the synthesized molecules as a new generation of improved antidepressants. Although remarkable advances have been made in cancer pharmacotherapy, the American Cancer Society declared this disease as the top killer of Americans in January, 2005. Therefore, a second research project presented herein focused on the development of a bivalent drug candidate for the treatment of cancer, which could combine into one molecular entity two distinct forms of cancer treatment, vascular disruption and bioreduction. Although the desired target molecule was not achieved, two unexpected and structurally unique products were obtained, which were fully characterized in regards to their structure. Preliminary biological evaluation indicates that compound 73 shows significant inhibition of tubulin assembly (IC50 = 3.3 microM), while compound 74 shows potent and selective in vitro cytotoxicity towards three human cancer cell lines. Therefore, the continuation of this line of research aimed at an improved treatment option for cancer patients is strongly encouraged.by M. Graciela Miranda.Ph.D