Synthesis and Biological Evaluation of Iodinated and Fluorinated 9-(2-Hydroxypropyl) and 9-(2-Hydroxyethoxy)methyl Purine Nucleoside Analogues

Abstract

The novel fluorinated and iodinated purine derivatives containing 9-(2-hydroxypropyl) (1a-7a and 9a-13a) and 9-(2-hydroxyethoxymethyl) (1b-3b, 5b, and 7b-12c) side chains were synthesized by a multistep synthetic route involving Baltz-Schiemann's fluorination and diazotation/iodination as key reactions. An unequivocal proof for the stereostructure of 5b was obtained by X-ray structure analysis. New compounds were evaluated for their cytostatic activity against murine leukemia (L1210); mammary carcinoma (FM3A); and human T-lymphocytes (Molt4/C8 and CEM), melanoma (HBL), cervical carcinoma (HeLa), colon carcinoma (HT29 and SW620), laryngeal carcinoma (Hep2), and pancreatic carcinoma (MiaPaCa2) as well as diploid fibroblasts (WI38). Of all the compounds, the 2-aminopurin-6-thione derivative 9a showed the most pronounced inhibitory activity against human SW620 cells. The 2-aminopurin-6-thione derivative 9b exhibited the most selective inhibitory activity against human HeLa, Hep2, SW620, and murine L1210 cell proliferation as compared to normal fibroblast (WI38) cell proliferation. None of the compounds showed inhibitory activities against HIV-1, HIV-2, HSV-1, and HSV-2, vaccinia, vesicular stomatitis, parainfluenza-3, reovirus-1, Sindbis, Coxsackie B4, or respiratory syncytial virus. The new purine derivatives, and particularly 9a and 9b, appear to demonstrate sufficient cytostatic potency and selectivity to justify further evaluation of their potential.

Synthesis and applications of fluorinated nucleoside analogues

“…To obtain [ 18 F]-labelled tracers the tosylated and methoxytritylated precursors were radiolabelled with a K[ 18 F]F/Kryptofix 2.2.2 complex in acetonitrile, followed by splitting off the protection groups under acidic conditions (Scheme 48). Raic-Malic and her research group [100] synthesized other types of fluorinated acyclic nucleoside analogues containing a 9-(2-hydroxypropyl) side chain (compound 264a) and a 9-(2-hydroxyethoxymethyl) side chain (compounds 264b and 261) by a multistep synthetic route involving Balz-Schiemann's fluorination as a key reaction. Introduction of fluorine in position C-2 of the purine ring in 260a, 260b, 263a, and 263b was performed using 60% HF/pyridine and t-butyl nitrite in nonaqueous media (Scheme 49).…”

The Pharmaceutical Biochemistry Group: Where Pharmaceutical Chemistry Meets Biology and Drug Delivery

“…[31] Our research focuses on characterizing the molecular mechanism governing the broad substrate specificity of HSV1 TK compared to human cytosolic TK [32][33][34][35][36][37][38] in order to address the problem of resistance towards antiviral compounds and the clinical limitations such as immunogenicity and treatment incompatibility discovered during the clinical application of the suicide gene approach based on HSV1 TK/ ganciclovir [39] using the interdisciplinary approach of the group. An effort has been made in order to design and develop new PET tracers for monitoring cancer and stem cells in vivo [40][41][42][43] in collaboration with Prof. Ametamey of the ETHZ. .…”

Synthesis and substitution reactions of β-alkoxyvinyl bromodifluoromethyl ketones

“…The ability of fluorine atom to enhance biological and therapeutic activities of organic compounds has led to widespread interest in selective introduction of fluorine atom and fluoroalkyl groups into organic molecules [1][2][3], especially those heterocyclic compounds which have potential biological activities. Recently, the introduction of the difluoromethylene moiety into organic compounds has been proved to be attractive due to the potential biological properties of such molecules [4][5][6].…”