The new 5- or 6-azapyrimidine and cyanuric acid derivatives of l-ascorbic acid bearing the free C-5 hydroxy or C-4 amino group at the ethylenic spacer: CD-spectral absolute configuration determination and biological activity evaluations (original) (raw)
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Ascorbic acid and 6-deoxy-6-chloro-ascorbic acid: potential anticancer drugs
Neoplasma, 1997
The role of ascorbic acid (AA) in prevention and suppression of carcinogenesis has been known for a long time. It was also found that AA may inhibit the growth of some tumor cells in vitro and in vivo. We examined the influence of ascorbic acid and 6-chloro-6-deoxy ascorbic acid (6-Cl-AA) on the growth of various human cell lines: lung fibroblasts (Hef), ovarian adenocarcinoma (OVCAR), colon adenocarcinoma (HT-29), laryngeal carcinoma (HEp2) cells, HEp2 cells resistant to vincristine (HEp2VA3), cervical carcinoma (HeLa) cells, HeLa cells resistant to cisplatin (Helacis), breast adenocarcinoma (SK-BR-3) cells, and SK-BR-3 resistant to doxorubicin (SK-BR-3-Dox), as well as mouse fibroblasts L929, mouse melanoma B16 (Mel B16) cells and Chinese hamster fibroblasts (V79). Both drugs arrested the growth of: HeLa, SK-BR-3, SK-BR-3-Dox, L929, and Mel B16 cells, but did not influence the growth of others: Hef, OVCAR, HEp2, HEp2VA3 and V79. 6-Cl-AA suppressed more the proliferation of HeLacis...
Bioorganic & Medicinal Chemistry, 2012
Several novel 1,2,4-triazole and imidazole L-ascorbic acid (1, 2, 3, 5, 6 and 9) and imino-ascorbic acid (4, 7 and 8) derivatives were prepared and evaluated for their inhibitory activity against hepatitis C virus (HCV) replication and human tumour cell proliferation. Compounds 6 and 9 exerted the most pronounced cytostatic effects in all tumour cell lines tested, and were highly selective for human T-cell acute lymphoblastic leukaemia cells (CEM/0) with IC 50 s of 10 ± 4 and 7.3 ± 0.1 lM, respectively. Unlike compound 9, compound 6 showed no toxicity in human diploid fibroblasts. One of the possible mechanisms of action of compound 6 accounting for observed cytostatic activity towards haematological malignancies might be inhibition of inosine monophosphate dehydrogenase (IMPDH) activity, a key enzyme of de novo purine nucleotide biosynthesis providing the cells with precursors for DNA and RNA synthesis indispensable for cell growth and division, which has emerged as an important target for antileukemic therapy. In addition, this compound proved to be the most potent inhibitor of the hepatitis C virus replication as well. However, observed antiviral effect was most likely associated with the effect that the compound exerted on the host cell rather than with selective effect on the replication of the virus itself. In conclusion, results of this study put forward compound 6 as a potential novel antitumor agent (IMPDH inhibitor) for treating leukaemia. Its significant biological activity and low toxicity in human diploid fibroblasts encourage further development of this compound as a lead.
Ascorbic acid: Chemistry, biology and the treatment of cancer
Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, 2012
Since the discovery of vitamin C, the number of its known biological functions is continually expanding. Both the names ascorbic acid and vitamin C reflect its antiscorbutic properties due to its role in the synthesis of collagen in connective tissues. Ascorbate acts as an electron-donor keeping iron in the ferrous state thereby maintaining the full activity of collagen hydroxylases; parallel reactions with a variety of dioxygenases affect the expression of a wide array of genes, for example via the HIF system, as well as via the epigenetic landscape of cells and tissues. In fact, all known physiological and biochemical functions of ascorbate are due to its action as an electron donor. The ability to donate one or two electrons makes AscH − an excellent reducing agent and antioxidant. Ascorbate readily undergoes pH-dependent autoxidation producing hydrogen peroxide (H 2 O 2). In the presence of catalytic metals this oxidation is accelerated. In this review, we show that the chemical and biochemical nature of ascorbate contribute to its antioxidant as well as its prooxidant properties. Recent pharmacokinetic data indicate that intravenous (i.v.) administration of ascorbate bypasses the tight control of the gut producing highly elevated plasma levels; ascorbate at very high levels can act as prodrug to deliver a significant flux of H 2 O 2 to tumors. This new knowledge has rekindled interest and spurred new research into the clinical potential of pharmacological ascorbate. Knowledge and understanding of the mechanisms of action of pharmacological ascorbate bring a rationale to its use to treat disease especially the use of i.v. delivery of pharmacological ascorbate as an adjuvant in the treatment of cancer.
European Journal of Medicinal Chemistry, 2015
Keeping the potential synergy of biological activity of synthetic anomalous derivatives of deazapurines and L-ascorbic acid (L-AA) in mind, we have synthesized new 3-, 7-and 9-deazapurine derivatives of Lascorbic (1e4, 8e10, 13e15) and imino-L-ascorbic acid (5e7, 11, 12, 16e19). These novel compounds were evaluated for their cytostatic and antiviral activity in vitro against a panel of human malignant tumour cell lines and normal murine fibroblasts (3T3). Among all evaluated compounds, the 9-deazapurine derivative of L-AA (13) exerted the most potent inhibitory activity on the growth of CEM/0 cells (IC 50 ¼ 4.1 ± 1.8 mM) and strong antiproliferative effect against L1210/0 (IC 50 ¼ 4.7 ± 0.1 mM) while the 9deazahypoxanthine derivative of L-AA (15) showed the best effect against HeLa cells (IC 50 ¼ 5.6 ± 1.3 mM) and prominent effect on L1210/0 (IC 50 ¼ 4.5 ± 0.5 mM). Furthermore, the 9-deazapurine derivative disubstituted with two imino-L-AA moieties (18) showed the best activity against L1210/0 tumour cells (IC 50 ¼ 4.4 ± 0.3 mM) and the most pronounced antiproliferative effects against MiaPaCa-2 cells (IC 50 ¼ 5.7 ± 0.2 mM). All these compounds showed selective cytostatic effect on tumour cell lines in comparison with embryonal murine fibroblasts (3T3). When evaluating their antiviral activity, the 3deazapurine derivative of L-AA (3) exhibited the highest activity against both laboratory-adapted strains of human cytomegalovirus (HCMV) (AD-169 and Davis) with EC 50 values comparable to those of the well-known anti-HCMV drug ganciclovir and without cytotoxic effects on normal human embryonal lung (HEL) cells.
Cancer Chemotherapy and Pharmacology, 2011
Purpose While the benefits of ascorbic acid (vitamin C, ascorbate) as an essential nutrient are well established, its effects on tumor cells and in tumor treatment are controversial. In particular, conflicting data exist whether ascorbate may increase the cytotoxic effects of antineoplastic drugs or may rather exert adverse effects on drug sensitivity during cancer treatment. Findings are further obscured regarding the distinction between ascorbate and dehydroascorbate (DHA). Thus, the purpose of this study was to evaluate and directly compare the cytotoxic efficacy of ascorbate compared to DHA, and to analyse if ascorbate at pharmacological concentrations affects the efficacy of antineoplastic agents in prostate carcinoma cells. Methods We directly compare the effects of ascorbate (supplied as ‘Pascorbin® solution for injection’) and DHA on tumor cell viability, and determine IC50 values for various cell lines. At concentrations well below the IC50, ascorbate effects on cell proliferation and cell cycle are analysed. We furthermore determine changes in cellular sensitivity towards various cytostatic drugs upon pre-treatment of cells with ascorbate. Results We demonstrate higher therapeutic efficacy of ascorbate over DHA in various cell lines, independent of cell line-specific differences in ascorbate sensitivity, and identify the extracellular generation of H2O2 as critical mechanism of ascorbate action. We furthermore show that, in addition to pro-apoptotic effects described previously, ascorbate treatment already at concentrations well below the IC50 exerts anti-proliferative effects on tumor cells. Those are based on interference with the cell cycle, namely by inducing a G0/G1 arrest. Pre-treatment of tumor cells with ascorbate leads to increased cellular sensitivity towards Docetaxel, Epirubicin, Irinotecan and 5-FU, but not towards Oxaliplatin and Vinorelbin. For Docetaxel and 5-FU, a linear correlation between this sensitizing effect and the ascorbate dosage is observed. Conclusions The redox-active form of vitamin C, ascorbate, shows therapeutic efficacy in tumor cells. These antitumor effects of ascorbate are mainly based on its extracellular action and, in addition to the induction of apoptosis, also include an anti-proliferative effect by inducing cell cycle arrest. Furthermore, ascorbate treatment specifically enhances the cytostatic potency of certain chemotherapeutics, which implicates therapeutic benefit during tumor treatment.
Ascorbic acid in cancer management – time for a second look
European Journal of Clinical and Experimental Medicine, 2023
Introduction and aim. Over the past decades, the hypotheses that ascorbic acid (AA) can play a role as an anti-neoplastic therapy have generated many conflicting reports. Despite the controversies, mounting evidence has shown that AA has the potential to play a role as an anti-neoplastic agent. Recent studies have unraveled its pharmacokinetics and various mechanism of action on cancer cells. This has spawned different preclinical studies with reports of good activities against various cancers. Material and methods. A review of the literature regarding ascorbic acid in the management of cancer was performed using the PubMed database. The research was limited to abstracts and available full-text articles. Analysis of the literature. Clinical trials have also demonstrated its safety and tolerability across different dosages. AA has been noted as a multitargeting agent that acts as a pro-oxidative cytotoxic agent, anti-cancer epigenetic regulator and immune modulator. AA has also been shown act synergistically with standard chemotherapy regimens in different cancers. Despite its potentials, phase III clinical trials are seriously lacking. The recent phase III VITALITY study shows that AA may play a role as an adjunct targeted therapy for ras-mutated cancers. Therefore, there is need to for more standardized clinical trials to help identify cancer subtypes and AA combination regimens that can show the most benefits. In this review, the pleiotropic mechanism of action of AA was explored as well as various preclinical and clinical studies in cancer therapy. In addition, recommendations were also made for effective strategies towards an AA and standard cancer regimens in treatment as well as future directions. Ascorbic acid has been shown to induce cell death in various cancer types through different mechanisms of action. Several clinical trials and case reports have shown its efficacy in combination chemotherapy, and the pharmacological route of action can be either intravenous or oral. However, it can impair the actions of some drugs when given in combination. Also, dosage should be determined for maximal pharmacologic action. Conclusion. Ascorbic acid has the potential to provide safe and cost-effective antineoplastic treatment option especially in combination therapy. Its potential needs to be further investigated through clinical trials.
Ascorbic Acid in Cancer: A Renewed Hope?
Journal of Cancer Science & Therapy, 2014
Ascorbic acid (AA), long known to treat scurvy, has had debatable use as an anti-neoplastic drug in the past. However recent in vitro and in vivo studies have revealed previously unexplored mechanisms through which AA selectively damages cancer cells without causing damage to normal cells. In view of newly emerging evidence, many clinical trials have been designed to study these effects in patients with different types of cancers. Promising results from these initial trials are giving renewed hope to the use of AA as an adjuvant to the conventional chemotherapeutic drugs to treat cancer, to alleviate toxicity from the treatment and to reduce patient morbidity.
Ascorbate as a Bioactive Compound in Cancer Therapy: The Old Classic Strikes Back
Molecules
Cancer is a disease of high mortality, and its prevalence has increased steadily in the last few years. However, during the last decade, the development of modern chemotherapy schemes, new radiotherapy techniques, targeted therapies and immunotherapy has brought new hope in the treatment of these diseases. Unfortunately, cancer therapies are also associated with frequent and, sometimes, severe adverse events. Ascorbate (ascorbic acid or vitamin C) is a potent water-soluble antioxidant that is produced in most mammals but is not synthesised endogenously in humans, which lack enzymes for its synthesis. Ascorbate has antioxidant effects that correspond closely to the dose administered. Interestingly, this natural antioxidant induces oxidative stress when given intravenously at a high dose, a paradoxical effect due to its interactions with iron. Importantly, this deleterious property of ascorbate can result in increased cell death. Although, historically, ascorbate has been reported to ...
On the Efficacy of High-dose Ascorbic Acid as Anticancer Treatment: A Literature Survey
Vitamin C (ascorbic acid, ascorbate) has a controversial history in cancer treatment. Emerging evidence indicates that ascorbate in cancer treatment deserves re-examination. As research results concerning ascorbate pharmacokinetics and its mechanisms of action against tumor cells have been published, and as evidence from case studies has continued to mount that ascorbate therapy could be effective if the right protocols were used, interest among physicians and scientists has increased.