Synthesis and in vitro antiproliferative evaluation of novel N-alkylated 6-isobutyl- and propyl pyrimidine derivatives.

A series of novel N-alkylated C-6-isobutyl- or -propyl pyrimidine derivatives were synthesized and their antiproliferative effect was evaluated on a panel of tumor cell lines including leukemia cell line K562 and normal diploid human fibroblasts. N-methoxymethylated 5-methylpyrimidin-2,4-dione with di(benzyloxy)isobutyl at C-6 (14b) showed the strongest effect on the cell growth at micromolar concentrations. Mechanisms of action for the lipophilic compound 14b predicted in silico, pointed to its anticancer and antimetastatic potential exerted through inhibition of DNA or RNA polymerases and adhesion molecules. The latter mechanism has been supported in vitro for adherent tumor cell lines.

[1]  P. Johnston,et al.  Characterization of p53 Wild-Type and Null Isogenic Colorectal Cancer Cell Lines Resistant to 5-Fluorouracil, Oxaliplatin, and Irinotecan , 2004, Clinical Cancer Research.

[2]  Luca Scorrano,et al.  A novel mitochondriotoxic small molecule that selectively inhibits tumor cell growth. , 2002, Cancer cell.

[3]  E. De Clercq,et al.  Synthesis, 18F‐Radiolabelling and Biological Evaluations of C‐6 Alkylated Pyrimidine Nucleoside Analogues , 2004, Nucleosides, nucleotides & nucleic acids.

[4]  E. De Clercq,et al.  Antiviral and Cytostatic Evaluation of the Novel 6-acyclic Chain Substituted Thymine Derivatives , 2005, Antiviral Chemistry & Chemotherapy.

[5]  A. Karlsson,et al.  Substrate specificity and phosphorylation of antiviral and anticancer nucleoside analogues by human deoxyribonucleoside kinases and ribonucleoside kinases , 2003, Pharmacology & Therapeutics.

[6]  R. Loddo,et al.  A Novel Synthetic Route for the Anti‐HIV Drug MC‐1220 and its Analogues , 2010, ChemMedChem.

[7]  G. Zadeh,et al.  Investigation of the In Vitro Therapeutic Efficacy of Nilotinib in Immortalized Human NF2-Null Vestibular Schwannoma Cells , 2012, PloS one.

[8]  A. Amr,et al.  Anticancer activities of some newly synthesized pyridine, pyrane, and pyrimidine derivatives. , 2006, Bioorganic & medicinal chemistry.

[9]  Sanja Koštrun,et al.  Modeling cellular pharmacokinetics of 14- and 15-membered macrolides with physicochemical properties. , 2011, Journal of medicinal chemistry.

[10]  X. Thomas.  Philadelphia chromosome-positive leukemia stem cells in acute lymphoblastic leukemia and tyrosine kinase inhibitor therapy. , 2012, World journal of stem cells.

[11]  E. Staren,et al.  Adhesion and migration of extracellular matrix-stimulated breast cancer. , 2003, The Journal of surgical research.

[12]  C. Spears,et al.  Unusual cytotoxicities of 5-(acylethynyl)-1-(2-hydroxyethoxy)methyluracils , 1996 .

[13]  Sally A Amundson,et al.  Roles for p53 in growth arrest and apoptosis: putting on the brakes after genotoxic stress , 1998, Oncogene.

[14]  S. Ametamey,et al.  Synthesis and Characterization of a C(6) Nucleoside Analogue for the in vivo Imaging of the Gene Expression of Herpes Simplex Virus Type‐1 Thymidine Kinase (HSV1 TK) , 2006, Chemistry & biodiversity.

[15]  K. Kinzler,et al.  Disruption of p53 in human cancer cells alters the responses to therapeutic agents. , 1999, The Journal of clinical investigation.

[16]  K. Konstantopoulos,et al.  PDGF Suppresses the Sulfation of CD44v and Potentiates CD44v-Mediated Binding of Colon Carcinoma Cells to Fibrin under Flow , 2012, PloS one.

[17]  S. Ametamey,et al.  A new N-methyl thymine derivative comprising a dihydroxyisobutenyl unit as ligand for thymidine kinase of herpes simplex virus type 1 (HSV-1 TK). , 2011, Bioorganic & medicinal chemistry letters.

[18]  Tatjana Gazivoda Kraljević,et al.  Syntheses and Antitumor Evaluation of C(6)‐Isobutyl‐ and C(6)‐Isobutenyl‐Substituted Pyrimidines, and Dihydropyrrolo[1,2‐c]pyrimidine‐1,3‐diones , 2011 .

[19]  T. Tolstikova,et al.  Antiarrhythmic activity of 4,6-di(het)aryl-5-nitro-3,4-dihydropyrimidin-(1H)-2-ones and its effects on arterial pressure in rats. , 2006, Bioorganic & medicinal chemistry letters.

[20]  F. Gago,et al.  N1-substituted thymine derivatives as mitochondrial thymidine kinase (TK-2) inhibitors. , 2006, Journal of medicinal chemistry.

[21]  Diaa A Ibrahim,et al.  Design, synthesis, and biological evaluation of novel pyrimidine derivatives as CDK2 inhibitors. , 2010, European journal of medicinal chemistry.

[22]  Tatjana Gazivoda Kraljević,et al.  Synthesis and evaluation of a C-6 alkylated pyrimidine derivative for the in vivo imaging of HSV1-TK gene expression. , 2012, Nuclear medicine and biology.

[23]  Rangappa S. Keri,et al.  Analgesic, anti-pyretic and DNA cleavage studies of novel pyrimidine derivatives of coumarin moiety. , 2010, European journal of medicinal chemistry.

[24]  S. Drabu,et al.  Synthesis of cyanopyridine and pyrimidine analogues as new anti-inflammatory and antimicrobial agents. , 2011, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[25]  O. Al-Deeb,et al.  Synthesis of novel 6-phenyl-2,4-disubstituted pyrimidine-5-carbonitriles as potential antimicrobial agents. , 2011, European journal of medicinal chemistry.

[26]  N. Curtin,et al.  The impact of p53 status on cellular sensitivity to antifolate drugs. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[27]  J. Plavec,et al.  Synthesis, Structural Studies and Antitumoral Evaluation of C-6 Alkyl and Alkenyl Side Chain Pyrimidine Derivatives , 2009, Molecules.

[28]  K. Pavelić,et al.  Novel C-6 fluorinated acyclic side chain pyrimidine derivatives: synthesis, (1)H and (13)C NMR conformational studies, and antiviral and cytostatic evaluations. , 2007, Journal of medicinal chemistry.

[29]  Riham F. George,et al.  Synthesis, analgesic and anti-inflammatory activities evaluation of some bi-, tri- and tetracyclic condensed pyrimidines. , 2009, European journal of medicinal chemistry.

[30]  D. Tyrrell,et al.  Design and synthesis of novel 5-substituted acyclic pyrimidine nucleosides as potent and selective inhibitors of hepatitis B virus. , 2002, Journal of medicinal chemistry.

[31]  Tatjana Gazivoda Kraljević,et al.  Synthesis, X-ray crystal structure study and antitumoral evaluations of 5,6-disubstituted pyrimidine derivatives. , 2010, Bioorganic & medicinal chemistry.

[32]  J. Shim,et al.  Functional analysis of pyrimidine biosynthesis enzymes using the anticancer drug 5‐fluorouracil in Caenorhabditis elegans , 2009, The FEBS journal.

[33]  D. Shang,et al.  Anticancer mechanisms of temporin-1CEa, an amphipathic α-helical antimicrobial peptide, in Bcap-37 human breast cancer cells. , 2013, Life sciences.

[34]  E. De Clercq,et al.  Palladium-catalyzed synthesis of [E]-6-(2-acylvinyl)uracils and [E]-6-(2-acylvinyl)-1-[(2-hydroxyethoxy)methyl]uracils--their antiviral and cytotoxic activities. , 1997, Bioorganic & medicinal chemistry.

[35]  L. Naesens,et al.  Synthesis, cytostatic and anti-HIV evaluations of the new unsaturated acyclic C-5 pyrimidine nucleoside analogues , 2008, Bioorganic & Medicinal Chemistry.

[36]  Tatjana Gazivoda Kraljević,et al.  Methoxymethyl (MOM) Group Nitrogen Protection of Pyrimidines Bearing C-6 Acyclic Side-Chains , 2011, Molecules.