Design, Synthesis And Biological Activity Of Novel Acenaphtho "1,2-b"Pyrrole And Naphthalimide Antitumor Agents

In the dissertation, three series of acenaphtho[1,2-b]pyrrole or naphthalimide derivatives were designed and synthesized. They were evaluated of their antitumor potency and confirmed of their mechanism of action. Comparing with their analogs reported before, several compounds were proved to possess novel molecular targets like fibroblast growth factor receptor 1 (FGFR1), lysosomal membrane permeabilization (LMP).In the first section, the antitumor activities of acenaphtho[1,2-b]pyrrole derivatives were studied. Twenty target compounds were designed and synthesized by introduction of sulfur, nucleophiles at 3-position, and/or by esterification with bromide/iodide at the 9-position. This novel series of acenaphtho[1,2-b]pyrrole derivatives were discovered as FGFR1 inhibitors with submicormolar to double digital nanomolar IC50 values and exhibited outstanding growth inhibition property in vitro with micromolar to double digital nanomolar IC50 values. The structure-activity relationship (SAR) studies showed that acenaphtho[1,2-b]pyrrole-carboxylic acid esters (2a-d) possess distinguished FGFR1 inhibition activity, e.g. compound 2b showed IC50 values of 19 nM. The thiol derivatives of the esters (3a-h) could also be great FGFR1 inhibitors with submicromolar IC50 values which varied with 3-position substitution. Additionally, compounds 2a-b were validated for their excellent selectivity against diverse kinases, like VEGFRs and PDGFRs. The antiproliferative results were quite consistent with their FGFR1 inhibition activities, especially for compound 2a-d and 3a-h. Molecular docking simulation demonstrated that compounds 2a-b occupied the ATP-binding domain. After all, these are the first examples of FGFR1 inhibitors based on acenaphtho[1,2-b]pyrrole scaffold.In the second section, the antitumor activities of multitarget naphthalimide derivatives were studied. Eight novel compounds were designed and synthesized by functionalizing the naphthalimide core at the 2-and 6-positons with polyamines and long alkyl chains. Besides,4 compounds were synthesized as reference. Majority of compounds 7a-d and 8a-d potently inhibited the growth of the five tested cancer cell lines with IC50 values ranging from 2 to 10?M and are more active than Amonafide. These compounds were tested for their interactions with DNA and their cell-free topo II inhibition activities, which demonstrated these compounds were weak DNA binders but modest topo?inhibitors. Furthermore, compounds 7b-d were found to notably induce LMP, and exhibited better antiproliferative activity comparing with their single-target analogs. All the newly-synthesized compounds were demonstrated to efficiently induce apoptosis via a mitochondrial pathway. Accordingly, a new paradigm was suggested for the design of novel multitarget anticancer drugs.In the third section, the antitumor activities of naphthalimide-cyclam conjugates with alkyl chains were studied. Five novel compounds were designed and synthesized by functionalizing the naphthalimide core at the 2-and 6-positons with cyclam and alkyl chains. They exhibited potent growth inhibition property in vitro with the IC50 values of 1005-10-6 M. These compounds were demonstrated to be quite modest DNA binders according to circular dichroism (CD) spectra and DNA relaxation assay, but quite potent topo?inhibitors in cell-free system due to kDNA decatenation assay. Besides, the length of alkyl chains could be utilized to adjust the binding of the compounds towards DNA and topo?. All the newly-synthesized compounds were demonstrated to efficiently induce apoptosis.