ABSTRACT
In an effort to develop potent, orally bioavailable compounds for the treatment of neoplastic diseases, we developed a class of dual VEGFR-2 kinase and tubulin inhibitors. Targeting the VEGFR receptor kinase and tubulin structure allows for inhibition of both tumor cells and tumor vasculature. Previously, a combination of two compounds, a VEGF receptor tyrosine kinase inhibitor and tubulin agent, was demonstrated to produce an enhanced antitumor response in animal studies. We have reaffirmed their results, with the added benefit that both activities are found in one compound.
ABSTRACT
Oxadiazole derivatives were synthesized and evaluated for their ability to inhibit tubulin polymerization and to cause mitotic arrest in tumor cells. The most potent compounds inhibited tubulin polymerization at concentrations below 1 microM. Lead analogs caused mitotic arrest of A431 human epidermoid cells and cells derived from multi-drug resistant tumors (10, EC(50)=7.8 nM). Competition for the colchicine binding site and pharmacokinetic properties of selected potent compounds were also investigated and are reported herein, along with structure-activity relationships for this novel series of antimitotic agents.
Subject(s)
Antimitotic Agents/chemical synthesis , Antimitotic Agents/pharmacology , Oxadiazoles/chemistry , Oxadiazoles/pharmacology , Tubulin/chemistry , Tubulin/metabolism , Animals , Antimitotic Agents/chemistry , Antimitotic Agents/classification , Biopolymers/chemistry , Biopolymers/metabolism , Cell Line, Tumor , Humans , Inhibitory Concentration 50 , Mice , Molecular Structure , Oxadiazoles/chemical synthesis , Oxadiazoles/classification , Protein Conformation/drug effects , Structure-Activity RelationshipABSTRACT
A novel triazole-containing chemical series was shown to inhibit tubulin polymerization and cause cell cycle arrest in A431 cancer cells with EC(50) values in the single digit nanomolar range. Binding experiments demonstrated that representative active compounds of this class compete with colchicine for its binding site on tubulin. The syntheses and structure-activity relationship studies for the triazole derivatives are described herein.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Triazoles/chemistry , Triazoles/pharmacology , Tubulin Modulators/chemistry , Tubulin Modulators/pharmacology , Antineoplastic Agents/chemical synthesis , Humans , Microtubules/drug effects , Molecular Structure , Structure-Activity Relationship , Triazoles/chemical synthesis , Tubulin Modulators/chemical synthesis , Tumor Cells, CulturedABSTRACT
Many cellular components are transported using a combination of the actin- and microtubule-based transport systems. However, how these two systems work together to allow well-regulated transport is not clearly understood. We investigate this question in the Xenopus melanophore model system, where three motors, kinesin II, cytoplasmic dynein, and myosin V, drive aggregation or dispersion of pigment organelles called melanosomes. During dispersion, myosin V functions as a "molecular ratchet" to increase outward transport by selectively terminating dynein-driven minus end runs. We show that there is a continual tug-of-war between the actin and microtubule transport systems, but the microtubule motors kinesin II and dynein are likely coordinated. Finally, we find that the transition from dispersion to aggregation increases dynein-mediated motion, decreases myosin V--mediated motion, and does not change kinesin II--dependent motion. Down-regulation of myosin V contributes to aggregation by impairing its ability to effectively compete with movement along microtubules.
