Sulfonyl-containing aldophosphamide analogues as novel anticancer prodrugs targeted against cyclophosphamide-resistant tumor cell lines.
نویسندگان
چکیده
A series of sulfonyl-group containing analogues of aldophosphamide (Aldo) were synthesized as potential anticancer prodrugs that liberate the cytotoxic phosphoramide mustards (PM, IPM, and tetrakis-PM) via beta-elimination, a nonenzymatic activation mechanism. Kinetic studies demonstrated that all these compounds spontaneously liberate phosphoramide mustards with half-lives in the range of 0.08-15.2 h under model physiological conditions in 0.08 M phosphate buffer at pH 7.4 and 37 degrees C. Analogous to Aldo, the rates of beta-elimination in all compounds was enhanced in reconstituted human plasma under same conditions. The compounds were more potent than the corresponding phosphoramide mustards against V-79 Chinese hamster lung fibroblasts in vitro (IC(50) = 1.8-69.1 microM). Several compounds showed excellent in vivo antitumor activity in CD2F1 mice against both P388/0 (Wild) and P388/CPA (CP-resistant) tumor cell lines.
منابع مشابه
Design and Synthesis of Novel Triazole-based Peptide Analogues as Anticancer Agents
Cancer disease is a great concern in the worldwide public health and current treatments do not give satisfactory results, so, developing novel therapeutic agents to combat cancer is highly demanded. Nowadays, anticancer peptides (ACPs) are becoming promising anticancer drug candidates. This is due to several advantages inherited in peptide molecules, such as being usually with small size, high ...
متن کاملDesign and Synthesis of Novel Triazole-based Peptide Analogues as Anticancer Agents
Cancer disease is a great concern in the worldwide public health and current treatments do not give satisfactory results, so, developing novel therapeutic agents to combat cancer is highly demanded. Nowadays, anticancer peptides (ACPs) are becoming promising anticancer drug candidates. This is due to several advantages inherited in peptide molecules, such as being usually with small size, high ...
متن کاملNovel Approach Synthesis, Molecular Docking and Cytotoxic Activity Evaluation of N-phenyl-2,2-dichloroacetamide Derivatives as Anticancer Agents
Dichloroacetate (DCA) as a small, cheap and available anticancer agent, is a pyruvate mimetic compound that stimulates the activity of pyruvate dehydrogenase (PDH) enzyme through inhibition of pyruvate dehydrogenase kinases (PDHK1-4). DCA turns on programed cell death (apoptosis) which suppressed in tumor cells and therefore inhibits tumor growth. DCA also interferes with the glucose uses of ca...
متن کاملSulfonyl-containing nucleoside phosphotriesters and phosphoramidates as novel anticancer prodrugs of 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP).
A series of sulfonyl-containing 5-fluoro-2'-deoxyuridine (FdU) phosphotriester and phosphoramidate analogues were designed and synthesized as anticancer prodrugs of FdUMP. Stability studies have demonstrated that these compounds underwent pH dependent beta-elimination to liberate the corresponding nucleotide species with half-lives in the range of 0.33-12.23 h under model physiological conditio...
متن کاملSelective ALDH3A1 Inhibition by Benzimidazole Analogues Increase Mafosfamide Sensitivity in Cancer Cells
Aldehyde dehydrogenase enzymes irreversibly oxidize aldehydes generated from metabolism of amino acids, fatty acids, food, smoke, additives, and xenobiotic drugs. Cyclophosphamide is one such xenobiotic used in cancer therapies. Upon activation, cyclophosphamide forms an intermediate, aldophosphamide, which can be detoxified to carboxyphosphamide by aldehyde dehydrogenases (ALDH), especially AL...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- Journal of medicinal chemistry
دوره 47 15 شماره
صفحات -
تاریخ انتشار 2004