Abstract
New inhibitors of tubulin polymerization and/or histone deacetylase (HDAC) activity were synthesized by attaching alkyl tethered hydroxamic acid appendages of varying length to oxazole-bridged combretastatin A-4 analogous caps. While their antiproliferative and microtubule disrupting effect was most pronounced for derivatives with short spacers, HDAC inhibition was strongest for those with longer spacers. These findings were further supported by computational methods such as structure-based docking experiments exploring the target interactions of the derivatives with varying linkers. For instance, compounds featuring short four-atom spacers between cap and hydroxamic acid inhibited the growth of various cancer cell lines and human endothelial hybrid cells with IC50 values in the low nanomolar range. In line with their ability to inhibit the microtubule assembly, four- and five-atom spacered hydroxamic acids caused an accumulation of 518A2 melanoma cells in G2/M phase, whereas a compound featuring a six-atom spacer and performing best in HDAC inhibition, induced a G1 arrest in these cells. All these beneficial anticancer activities together with their selectivity for cancer cells over non-malignant cells, point out the great potential of these novel pleiotropic HDAC and tubulin inhibitors as drug candidates for cancer therapy.
Highlights
Histone deacetylases (HDAC) catalyze the deacetylation of ε-N-acetyl lysine residues of histones regulating the expression of genes which are important for crucial cellular processes such as chromatin condensation and decondensation (DNA replication, transcription, and repair)
New inhibitors of tubulin polymerization and/or histone deacetylase (HDAC) activity were synthesized by attaching alkyl tethered hydroxamic acid appendages of varying length to oxazole-bridged combretastatin A-4 analogous caps
Chemistry The 4,5-diaryloxazoles were synthesized via a Van Leusen reaction
Summary
Histone deacetylases (HDAC) catalyze the deacetylation of ε-N-acetyl lysine residues of histones regulating the expression of genes which are important for crucial cellular processes such as chromatin condensation and decondensation (DNA replication, transcription, and repair). Certain HDAC enzymes modify non-histone proteins such as signal transduction mediators, transcription factors and regulators, as well as structural proteins resulting in modulation of cell growth, differentiation, migration, and angiogenesis [1]. HDACs are overexpressed in various solid tumors, e.g., in gastric cancer, prostate canIncte.rJ,. BMroel.aSscti.c2a0n19c,e1r9,,axnd colorectal cancer [2,3,4,5,6]. Acks, HDACi with dual or multimodal activities including kinMasicerionthuibuitiloens aoreDvNitAalaclokmylaptoionne/nmtsetoaflatthioencwyteorsekienltertoodnucaendd[1th7u].s an important target in cancer chemotMheicrraoptyub[u18le,s19a]r.e Ivnitaelrecsotminpgolyn,eHntDs oAfCthi ehcayvteosskheolewtonnsaynndertgheutsicanefifmecptsorwtahnet ntacrgoemt bininceadncwerith tubcuhleimn-obtihnedrianpgya[n1t8ic,1a9n]c.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
