ABSTRACT
A current study shows that sodium dichloroacetate (DCA) can induce cancer cell apoptosis and inhibit tumor growth, but its cytotoxic activity is low (IC(50) > 1000 microM for A549). In this paper, a variety of DCA derivatives were synthesized, and their cytotoxic activities were evaluated. The result showed that the N-phenyl-2,2-dichloroacetamide analogues had satisfactory potencies. Among them, N-(3-iodophenyl)-2,2-dichloroacetamide (3e), an optimized lead compound, has an IC(50) against A549 as low as 4.76 microM. Furthermore, it can induce cancer cell apoptosis and has a low toxicity in mice (LD(50) = 1117 mg/kg).
Subject(s)
Acetamides/chemistry , Acetamides/pharmacology , Acetanilides/chemistry , Acetanilides/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Drug Design , Acetamides/chemical synthesis , Acetamides/toxicity , Acetanilides/chemical synthesis , Acetanilides/toxicity , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/toxicity , Cell Line, Tumor , Female , Humans , Inhibitory Concentration 50 , Lethal Dose 50 , Male , Mice , Structure-Activity RelationshipABSTRACT
A general method is described for synthesizing 3',5'-dithio-2'-deoxypyrimidine nucleosides 6 and 13 from normal 2'-deoxynucleosides. 2,3'-Anhydronucleosides 2 and 9 are applied as intermediates in the process to reverse the conformation of 3'-position on sugar rings. The intramolecular rings of 2,3'-anhydrothymidine and uridine are opened by thioacetic acid directly to produce 3'-S-acetyl-3'-thio-2'-deoxynucleosides 3 or 5. To cytidine, OH(-) ion exchange resin was used to open the ring and 2'-deoxycytidine 10 was obtained in which 3'-OH group is in threo-conformation. The 3'-OH is activated by MsCl, and then substituted by potassium thioacetate to form the S,S'-diacetyl-3',5'-dithio-2'-deoxycytidine 12. The acetyl groups in 3',5' position are removed rapidly by EtSNa in EtSH solution to afford the target molecules 6 and 13. The differences of synthetic routes between uridine and cytidine are also discusssed.
Subject(s)
Deoxycytidine/chemistry , Deoxyuridine/chemistry , Nucleic Acids/chemistry , Deoxycytidine/chemical synthesis , Deoxyuridine/chemical synthesis , Magnetic Resonance Spectroscopy , Molecular Structure , Nucleic Acids/chemical synthesisABSTRACT
In the crystal structure of the title compound, C(11)H(14)ClNO(3), inter-molecular hydrogen bonds link mol-ecules in the ab plane, forming layers that stack along the c axis.
