Synthesis and in vitro antitumor activity of 4(3H)-quinazolinone derivatives with dithiocarbamate side chains
01 Apr 2005-Bioorganic & Medicinal Chemistry Letters (Bioorg Med Chem Lett)-Vol. 15, Iss: 7, pp 1915-1917
TL;DR: A series of 4(3H)-quinazolinone derivatives with dithiocarbamate side chains were synthesized and tested for their in vitro antitumor activity against human myelogenous leukemia K562 cells, and Piperazine-1-carbodithioate 8q exhibited significant inhibitory activity.
About: This article is published in Bioorganic & Medicinal Chemistry Letters.The article was published on 2005-04-01. It has received 325 citations till now. The article focuses on the topics: Dithiocarbamate & Quinazolinone.
Citations
More filters
TL;DR: Ionic Liquids Presented in This Review 2020 3.1.
Abstract: 2.5. Ionic Liquids Presented in This Review 2020 3. Cyclocondensation Reactions 2020 4. Synthesis of Three-Membered Heterocycles 2022 4.1. Aziridines 2022 5. Synthesis of Five-Membered Heterocycles 2022 5.1. Pyrroles 2022 5.2. Furans 2022 5.3. Thiophenes 2023 5.4. Pyrazoles 2024 5.5. Imidazoles 2025 5.6. Isoxazoles 2027 5.7. Oxazoles, Oxazolines, and Oxazolidinones 2027 5.8. Thiazoles and Thiazolidinones 2028 6. Synthesis of Six-Membered Heterocycles 2030 6.1. Pyridines 2030 6.2. Quinolines 2031 6.3. Acridines 2033 6.4. Pyrans 2033 6.5. Flavones 2035 6.6. Pyrimidines and Pyrimidinones 2035 6.7. Quinazolines 2037 6.8. -Carbolines 2038 6.9. Dioxanes 2039 6.10. Oxazines 2039 6.11. Benzothiazines 2040 6.12. Triazines 2040 7. Synthesis of Seven-Membered Heterocycles: Diazepines 2041
631 citations
TL;DR: An efficient synthesis of quinazolin-4(3H)-ones from N-arylamidines, through palladium-catalyzed intramolecular C(sp(2))-H carboxamidation, has been developed and features atom-economy and step-efficiency.
Abstract: An efficient synthesis of quinazolin-4(3H)-ones from N-arylamidines, through palladium-catalyzed intramolecular C(sp2)–H carboxamidation, has been developed. The reaction, carried out in the presence of 1.0 equiv of CuO as oxidant under atmospheric pressure of CO, provides diversified 2-aryl(alkyl)quinazolin-4(3H)-ones in reasonable to good yields from N-arylamidines, which are readily derived from anilines and nitriles. Compared with existing approaches to quinazolin-4(3H)-ones, the current strategy features atom-economy and step-efficiency.
160 citations
TL;DR: Novel 3-aryl-4(3H)-quinazolinone-2-carboxaldehydes, their corresponding Schiff's base and thiosemicarbazone derivatives were synthesized from the starting 5-iodo anthranilic acid and screened for some selected compounds to probe their potential anticonvulsant, analgesic, cytotoxic as well as their antimicrobial activities.
152 citations
TL;DR: Under these conditions other amides that were tested only provided simple coupling products, which can be converted into 2,3-disubstituted quinazolinones via HMDS/ZnCl(2) mediated condensative cyclization.
143 citations
TL;DR: The main theme of this review is neat reactions as mentioned in this paper, which are solvent and catalyst-free reactions in the absence of any solvent or catalyst with concise summaries of microwave, ball milling and neat reactions have been described.
136 citations
References
More filters
Journal Article•
TL;DR: The synthesis and activity of a novel cancer chemopreventive agent is reported, (+/-)-4-methylsulfinyl-1-(S-methyldithiocarbamyl)-butane (trivial name, sulforamate), an aliphatic analogue of brassinin with structural similarities to sulforaphane, which can be regarded as a readily available promising new cancer chemobiotic responsive agent.
Abstract: Chemoprevention involves the use of natural or synthetic substances to reduce the risk of developing cancer. Two dietary components capable of mediating chemopreventive activity in animal models by modulation of drug-metabolizing enzymes are sulforaphane, an aliphatic isothiocyanate, and brassinin, an indole-based dithiocarbamate, both found in cruciferous vegetables. We currently report the synthesis and activity of a novel cancer chemopreventive agent, (+/-)-4-methylsulfinyl-1-(S-methyldithiocarbamyl)-butane (trivial name, sulforamate), an aliphatic analogue of brassinin with structural similarities to sulforaphane. This compound was shown to be a monofunctional inducer of NAD(P)H:quinone oxidoreductase [quinone reductase (QR)], a Phase II enzyme, in murine Hepa 1c1c7 cell culture and two mutants thereof. Induction potential was comparable to that observed with sulforaphane (concentration required to double the specific activity of QR, approximately 0.2 microM), but cytotoxicity was reduced by about 3-fold (IC50 approximately 30 microm). In addition, sulforaphane, as well as the analogue, increased glutathione levels about 2-fold in cultured Hepa 1c1c7 cells. Induction of QR was regulated at the transcriptional level. Using Northern blotting techniques, time- and dose-dependent induction of QR mRNA levels were demonstrated in Hepa 1c1c7 cell culture. To further investigate the mechanism of induction, HepG2 human hepatoma cells were transiently transfected with QR-chloramphenicol acetyltransferase plasmid constructs containing various portions of the 5'-region of the QR gene. Sulforaphane and the analogue significantly induced (P < 0.0001) CAT activity at a concentration of 12.5 microM by interaction with the antioxidant responsive element (5-14-fold induction) without interacting with the xenobiotic responsive element. Moreover, both compounds significantly induced mouse mammary QR and glutathione S-transferase activity (feeding of 3 mg/mouse intragastric for 4 days), whereas the elevation of hepatic enzyme activities was less pronounced. Both sulforaphane and the analogue were identified as potent inhibitors of preneoplastic lesion formation in carcinogen-treated mouse mammary glands in organ culture (84 and 78% inhibition at 1 microm, respectively). On the basis of these results, the sulforaphane analogue can be regarded as a readily available promising new cancer chemopreventive agent.
248 citations
TL;DR: Brassinin may be effective as a chemopreventive agent during both the initiation and promotion phases of carcinogenesis, and the synthetic route described herein has proven amenable for scale-up production.
Abstract: Brassinin [3-(S-methyldithiocarbamoyl)aminomethyl indole], a phytoalexin first identified as a constituent of cabbage, was synthesized and evaluated for cancer chemopreventive activity Dose-dependent inhibition of 7,12-dimethylbenz[a]anthracene (DMBA)-induced preneoplastic lesion formation was observed with mouse mammary glands in organ culture, as was dose-dependent inhibition of DMBA-induced mouse skin tumors that were promoted by treatment with 12-O-tetradecanoylphorbol-13-acetate Cyclobrassinin is a biologically derived product of the oxidative cyclization of brassinin, and was as active as the parent compound in inhibiting the formation of preneoplastic mammary lesions in culture; however, 2-methylbrassinin was not significantly active in this process Therefore, oxidative cyclization may be an effective metabolic activation step As judged by these tumor inhibition studies in conjunction with potential to induce phase II enzymes in mice or cell culture, brassinin may be effective as a chemopreventive agent during both the initiation and promotion phases of carcinogenesis This is the first report documenting the chemopreventive potential of structurally novel indole-based phytoalexins that are naturally occurring in cruciferous vegetables, and the synthetic route described herein has proven amenable for scale-up production The bifunctional structural nature of brassinin, bearing both an indole nucleus and a dithiocarbamoyl-aminomethyl moiety, is notably similar to the individual structural elements of other known chemopreventive agents such as indole-3-carbinol or benzylisothiocyanate The favorable biological activity demonstrated by the compound may originate from the presence of these two moieties
209 citations
TL;DR: Preclinical studies indicate that the toxic effects of pemetrexed can be reduced by dietary folate, resulting in an improved therapeutic index and low folate status is also associated with higher levels of toxicity in patients.
Abstract: Pemetrexed disodium is a potent new antifolate which inhibits many folate-dependent reactions that are essential for cell proliferation. Its primary target is thymidylate synthase but it also inhibits folate-dependent enzymes involved in purine synthesis. Cells that are resistant to antifolates are generally less resistant to pemetrexed, irrespective of the mechanism of resistance. Pemetrexed has shown good activity in preclinical models with human tumour cells and xenografts. In the majority of clinical trials of pemetrexed, the dose-limiting toxic effect is neutropenia; other side-effects are mostly gastrointestinal. Preclinical studies indicate that the toxic effects of pemetrexed can be reduced by dietary folate, resulting in an improved therapeutic index. Low folate status is also associated with higher levels of toxicity in patients. As a single agent pemetrexed has shown good activity against non-small-cell lung cancer, squamous-cell carcinoma of head and neck, colon cancer, and breast cancer, and it appears to be particularly active in combination with cisplatin against non-small-cell lung cancer and mesothelioma. Phase II and III studies are underway.
97 citations
TL;DR: The enhanced cytotoxicities of the thiophene and thiazole analogues result, at least in part, from their efficient transport into the cells via the reduced folate carrier mechanism and very good substrate activity for folylpolyglutamate synthetase.
Abstract: The synthesis is described of a series of C2-methyl-N10-alkylquinazoline-based antifolates in which the p-aminobenzoate ring is replaced by the heterocycles thiophene, thiazole, thiadiazole, pyridine, and pyrimidine. These were generally elaborated by the reaction of (bromomethyl)quinazoline 18 or its N3-[(pivaloyloxy)methyl]-protected derivative 36 with suitable heterocyclic amines although each heterocyclic system required its own particular synthetic approach. The compounds were tested as inhibitors of partially purified L1210 thymidylate synthase (TS). They were also examined for their inhibition of the growth of L1210 cells in culture. The thiophene system 7 and its related thiazole 8 gave analogues that were considerably more potent than the parent benzene series 2 as inhibitors of L1210 cell growth although in general these heterocycles were somewhat poorer inhibitors of the isolated TS enzyme. The enhanced cytotoxicities of the thiophene and thiazole analogues result, at least in part, from their efficient transport into the cells via the reduced folate carrier mechanism and very good substrate activity for folylpolyglutamate synthetase. The replacement of the C2-methyl group by C2-(fluoromethyl) and C2-(hydroxymethyl) substituents in the thiophene and thiazole series gave derivatives that were only slightly less potent inhibitors of the TS enzyme but which were considerably less cytotoxic.
92 citations
TL;DR: In vivo, AG337 was highly active against the thymidine kinase-deficient murine L5178Y/TK- lymphoma implanted either i.p.m. or oral delivery, suggesting, as would be expected for a lipophilic agent, that there is rapid influx and efflux from cells and no intracellular metabolism to derivatives with enhanced retention.
Abstract: 3,4-Dihydro-2-amino-6-methyl-4-oxo-5-(4-pyridylthio)-quinazoline dihydrochloride (AG337) is a water-soluble, lipophilic inhibitor of thymidylate synthase (TS) designed using X-ray structure-based methodologies to interact at the folate cofactor binding site of the enzyme. The aim of the design program was to identify TS inhibitors with different pharmacological characteristics from classical folate analogs and, most notably, to develop non-glutamate-containing molecules which would not require facilitated transport for uptake and would not undergo intracellular polyglutamylation. One molecule which resulted from this program, AG337, inhibits purified recombinant human TS with a Ki of 11 nM, and displays non-competitive inhibition kinetics. It was further shown to inhibit cell growth in a panel of cell lines of murine and human origin, displaying an IC50 of between 0.39 μM and 6.6 μM. TS was suggested as the locus of action of AG337 by the ability of thymidine to antagonize cell growth inhibition and the direct demonstration of TS inhibition in whole cells using a tritium release assay. The demonstration, by flow cytometry, that AG337-treated L1210 cells were arrested in the S phase of the cell cycle was also consistent with a blockage of TS, as was the pattern of ribonucleotide and deoxyribonucleotide pool modulation in AG337-treated cells, which showed significant reduction in TTP levels. The effects of AG337 were quickly reversed on removal of the drug, suggesting, as would be expected for a lipophilic agent, that there is rapid influx and efflux from cells and no intracellular metabolism to derivatives with enhanced retention. In vivo, AG337 was highly active against the thymidine kinase-deficient murine L5178Y/TK- lymphoma implanted either i.p. or i.m. following i.p. or oral delivery. Prolonged dosing periods of 5 or 10 days were required for activity, and efficacy was improved with twice-daily dose administration. Dose levels of 25 mg/kg delivered i.p. twice daily for 10 days, 50 mg/kg once daily for 10 days, or 100 mg/kg once daily for 5 days elicited 100% cures against the i.p. tumor. Doses required for activity against the i.m. tumor were higher (100 mg/kg i.p. twice daily for 5 or 10 days) but demonstrated the ability of AG337 to penetrate solid tissue barriers. Oral delivery required doses of ≥150 mg/kg twice daily for periods of 5–10 days to produce 100% cure rates against both i.m. and i.p. implanted tumors. These results were consistent with the pharmacokinetic parameters determined in rats, for which oral bioavailability of 30–50% was determined, together with a relatively short elimination half life of 2 h. Clinical studies with AG337 are currently in progress.
86 citations