title: Modulating lipophilicity of rohitukine via prodrug approach: Preparation, characterization, and in vitro enzymatic hydrolysis in biorelevant media.
abstract: Rohitukine is a medicinally important natural product which has inspired the discovery of two anticancer clinical candidates. Rohitukine is highly hydrophilic in nature which hampers its oral bioavailability. Thus, herein our objective was to improve the drug-like properties of rohitukine via prodrug-strategy. Various ester prodrugs were synthesized and studied for solubility, lipophilicity, chemical stability and enzymatic hydrolysis in plasma/esterase. All prodrugs displayed lower aqueous solubility and improved lipophilicity compared with rohitukine, which was in accordance with the criteria of compounds in drug-discovery. The stability of synthesized prodrugs was evaluated in buffers at different pH, SGF, SIF, rat plasma and in esterase enzyme. The rate of hydrolysis in all incubation media was dependent primarily on the acyl promoieties. Hexanoyl ester prodrug of rohitukine, 3d, was stable under chemical conditions; however it was completely hydrolyzed to rohitukine, in plasma and in esterase in 4h. Hexanoate ester 3d appeared to be the most promising prodrug as it remained intact at gastric/intestinal pH and was completely transformed to the parent compound in plasma as desired for an ideal prodrug. The data presented herein, will help in designing prodrugs with desired physicochemical properties in future in structurally similar chemotypes.
authors.affiliation: Preformulation Laboratory, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India; Academy of Scientific and Innovative Research (AcSIR), CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India.
authors.forename: Vikas
authors.initials: V
authors.lastname: Kumar
authors.affiliation: Preformulation Laboratory, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India. Electronic address: sonalibharate@gmail.com.
authors.forename: Sonali S
authors.initials: SS
authors.lastname: Bharate
authors.affiliation: Academy of Scientific and Innovative Research (AcSIR), CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India; Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India. Electronic address: ram@iiim.ac.in.
authors.forename: Ram A
authors.initials: RA
authors.lastname: Vishwakarma
mesh_terms: D020003:1-Octanol / Q000737:chemistry; D000818:Animals; D002867:Chromones / Q000737:chemistry*; D004339:Drug Compounding; D004355:Drug Stability; D004950:Esterases / Q000737:chemistry; D004952:Esters; D005750:Gastric Juice / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D057927:Hydrophobic and Hydrophilic Interactions; D007419:Intestinal Secretions / Q000737:chemistry; D010880:Piperidines / Q000737:chemistry*; D010949:Plasma / Q000737:chemistry; D011355:Prodrugs / Q000737:chemistry*; D051381:Rats; D012995:Solubility; D014867:Water / Q000737:chemistry
chemical_list: C573233:5,7-dihydroxy-2-methyl-8-(4-(3-hydroxy-1-methyl)-piperidinyl)-4H-1-benzopyran-4-one; D002867:Chromones; D004952:Esters; D010880:Piperidines; D011355:Prodrugs; D014867:Water; D004950:Esterases; D020003:1-Octanol
keywords: Drug discovery; Enzymatic hydrolysis; Lipophilicity; Prodrugs; Rohitukine; Solubility