Design and structure activity relationship of tumor-homing histone deacetylase inhibitors conjugated to folic and pteroic acids

• Published in: European journal of medicinal chemistry 2015-05, Vol.96, p.340-359
• Main Authors: Sodji, Quaovi H., Kornacki, James R., McDonald, John F., Mrksich, Milan, Oyelere, Adegboyega K.
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Folate; Folic Acid - chemistry; Folic Acid - pharmacology; HeLa Cells; Histone deacetylase; Histone Deacetylase 1 - antagonists & inhibitors; Histone Deacetylase 1 - metabolism; Histone Deacetylase Inhibitors - chemical synthesis; Histone Deacetylase Inhibitors - chemistry; Histone Deacetylase Inhibitors - pharmacology; Humans; Hydroxamic acid; KB Cells; Models, Molecular; Molecular Structure; Pterins - chemistry; Pterins - pharmacology; Pteroic acid; Reactive Oxygen Species - metabolism; Structure-Activity Relationship; Targeted delivery; Tubastatin A
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2015.04.014

Histone deacetylase (HDAC) inhibition has recently emerged as a novel therapeutic approach for the treatment of various pathological conditions including cancer. Currently, two HDAC inhibitors (HDACi) – Vorinostat and Romidepsin – have been approved for the treatment of cutaneous T-cell lymphoma. However, HDACi remain ineffective against solid tumors and are associated with adverse events including cardiotoxicity. Targeted delivery may enhance the therapeutic indices of HDACi and enable them to be efficacious against solid tumors. We showed herein that morphing of folic and pteroic acids into the surface recognition group of HDACi results in hydroxamate and benzamide HDACi which derived tumor homing by targeting folate receptor (FR), a receptor commonly overexpressed in solid tumors. We observed a correlation between the potency of HDAC1 inhibition and cytotoxicity as only the potent pteroate hydroxamates, 11d and 11e, displayed antiproliferative activity against two representative FR-expression cancer cells. Our observation further supports the previous results which suggest that for a drug to be successfully targeted using the FR, it must be extremely potent against its primary target as the FR has a low delivery efficiency. [Display omitted] •Folate γ-hydroxamate is devoid of HDAC inhibition.•Pteroic hydroxamate is selective against HDAC6, though active against other isoforms such as HDAC1 and 8.•HDACi with pteroic acid (cap group) and hydroxamate (ZBG) are potent against HDAC1 and 6.•Pteroic based-hydroxamates had anticancer activity against FR(+) tumor cells (KB and HeLa).•HDAC1 inhibition results in KB cells death, whereas, HDAC6 does not.