Synthesis, In Vitro Cytotoxicity and Radiosensitizing Activity of Novel 3‐[(2, 4‐Dinitrophenylamino)Alkyl] Derivatives of 5‐Fluorouracil. (4th October 2013)

• Record Type: Journal Article
• Authors: Khalaj, Ali; Abdi, Khosrou; Ostad, Seyed Nasser; Khoshayand, Mohammad Reza; Lamei, Navid; Nedaie, Hasan Ali
• Is Part Of: Chemical biology & drug design. Volume 83:Number 2(2014:Feb.)
• Page Start: 183
• Page End: 190
• Publication Date: 2013-10-04
• Subjects: Drugs -- Design -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; 615.19005
• DOI: 10.1111/cbdd.12211
• Languages: English
• ISSNs: 1747-0277

Abstract

<abstract abstract-type="main" id="cbdd12211-abs-0001"> <title> <x xml:space="preserve">Abstract</x> </title> <p>Previously, it was reported that 3[3‐(2, 4‐dinitrophenylamino)‐propyl]‐5‐fluorouracil <bold>8c</bold> unlike its components 5‐fluorouracil (5‐FU) <bold>6</bold> and 2, 4‐dinitroaniline <bold>2</bold> in HT‐29 cells under aerobic conditions had no cytotoxicity but showed radiosensitizing activity. In this study several analogues of <bold>8c</bold> differing in the number of linking methylene groups were prepared and tested for <italic>in vitro</italic> cytotoxicity and radiosensitizing activity under both aerobic and hypoxic conditions. Tethered compound <bold>8a</bold> was prepared in one pot by the reaction of 5‐FU <bold>6</bold> with paraformaldehyde and 2, 4‐dinitroaniline <bold>2</bold> in the presence of the concentrated hydrochloric acid, and compounds <bold>8b–f</bold> were prepared by the reaction of N‐(bromoalkyl) ‐ 2, 4‐dinitrobenzeneamines <bold>5b–f</bold> with 1‐(<italic>t</italic>‐butoxycarbonyl)‐5‐fluorouracil <bold>7</bold> followed by hydrolysis of the protecting group. The cytotoxicity of the tested compounds were measured by 3‐(4, 5‐Dimethylthiazol‐2‐yl)‐2, 5‐diphenyltetrazolium bromide (MTT), and propidium iodide (PI)‐digitonin assays and values of sensitization enhancement ratio (SER) as a measure of the radiosensitizing activity were measured from radiation survival curves in the absence and presence of each sensitizer for 37% survival respectively. Results showed that tethered compounds <bold>8a–f</bold> induced time‐ and concentration‐dependent cytotoxicity under hypoxia but had no significant effect under aerobic conditions. These compounds also showed selective and concentration‐dependent radiocytotoxicity under hypoxic conditions.</p> </abstract>