DNA interstrand cross-linking (ICL) agents are an important group of cytotoxic drugs with the capability of binding covalently between two strands of DNA, thereby preventing vital processes such as replication or transcription in dividing cells. In anticancer therapy however, their potential is limited due to the resistance by various mechanisms. In order to develop highly effective antitumor drugs it is necessary to study both effective ICL formations and their subsequent repair mechanisms. This review presents an overview of development over the past decade and the use of both well-known and new DNA interstrand cross-linking agents. Their potential in applications especially as anticancer chemotherapeutics in the framework of current knowledge of repair mechanisms and development of combined chemotherapy is discussed.

• MeSH
• alkaloidy chemie   terapeutické užití   MeSH
• anthrachinony chemie   terapeutické užití   MeSH
• azepiny chemie   terapeutické užití   MeSH
• aziridiny chemie   terapeutické užití   MeSH
• DNA chemie   metabolismus   MeSH
• komplexní sloučeniny chemie   terapeutické užití   MeSH
• lidé MeSH
• mechlorethamin chemie   terapeutické užití   MeSH
• nádory farmakoterapie   MeSH
• oprava DNA MeSH
• protinádorové látky chemie   terapeutické užití   MeSH
• reagencia zkříženě vázaná chemie   terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

A number of 5-alkoxymethyluracil analogues were synthesized to evaluate their cytotoxic activity. 5-Alkoxymethyluracil derivatives 1 were prepared via known nucleophilic substitution of 5-chloromethyluracil 5 and subsequently transformed to their corresponding nucleosides 2. All prepared compounds were submitted to cytotoxic activity testing against drug sensitive and drug resistant leukaemia cells and solid tumour derived cell lines. In addition, the cytotoxic activity of 5-alkoxymethyluracil analogues 1 and 2 was compared with the previously published 5-[alkoxy(4-nitrophenyl)methyl]uracil analogues 3 and 4. Extensive structure-cytotoxic activity relationship studies are reported.

• MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• protinádorové látky chemická syntéza   chemie   farmakologie   MeSH
• uracil analogy a deriváty   chemická syntéza   chemie   farmakologie   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

A series of uridine analogues modified at the 5-position with the 5-[alkoxy-(4-nitrophenyl)-methyl] moiety was synthesized. Nucleosides were formed as a mixture of two diastereoisomers, which were separated and tested for their cytotoxic activity in vitro against different cancer cell lines and for antimicrobial activity. Relationships between structure and the above mentioned activities were studied. The cytotoxic activity was slightly increased in some cases by transformation of bases to nucleosides. Depending on the length of the alkyl chain increased cytotoxic and antimicrobial activity were noted. The cytotoxic activity of the nucleosides was not due to cell cycle alterations, DNA and/or RNA synthesis.

• MeSH
• Bacteria účinky léků   MeSH
• inhibiční koncentrace 50 MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• protinádorové látky chemická syntéza   chemie   farmakologie   MeSH
• uridin analogy a deriváty   chemická syntéza   farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The preparation of various 5-[alkoxy-(4-nitro-phenyl)-methyl]-uracils with alkyl chain lengths C(1)-C(12) is described. The synthesis is based on the preparation of 5-[chloro-(4-nitro-phenyl)-methyl]-uracil and subsequent substitution of chlorine with appropriate alcohols. The resulting ethers were tested for their cytotoxic activity in vitro against five cancer cell lines. The compounds were less active in lung resistance protein expressing cell lines, suggesting the involvement of this multidrug resistant protein in control of the biological activity. Cytotoxic substances induced rapid inhibition of DNA and modulation of RNA synthesis followed by induction of apoptosis. The data indicate that the biological activity of 5-[alkoxy-(4-nitro-phenyl)-methyl]-uracils depends on the alkyl chain length.

• MeSH
• alkoholy chemická syntéza   toxicita   MeSH
• buňky K562 MeSH
• cytotoxiny chemická syntéza   toxicita   MeSH
• financování organizované MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• protinádorové látky chemická syntéza   toxicita   MeSH
• stereoizomerie MeSH
• uracil analogy a deriváty   chemická syntéza   toxicita   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• srovnávací studie MeSH