Straightforward synthesis of cytosporone analogs AMS35AA and AMS35BB.

Cytosporones, a class of octaketide resorcinolic lipids, have drawn the attention of researchers for exhibiting a number of notable biological properties. Herein, we describe routes to synthesize the bioactive synthetic resorcinolic lipids AMS35AA and AMS35BB with excellent overall yields using 3,5-dimethoxybenzoic acid as the starting material. The methods proved remarkably efficient to achieve the target compounds and comprise the synthesis of AMS35AA catalyzed by ascorbic acid (vitamin C).

Effects of 3-Heptyl-3,4,6-trimethoxy-3H-isobenzofuran-1-one alone or/in association with cyclophosphamide on testicular function.

Chemotherapy for cancer treatment may result in a temporary or long-term gonadal damage resulting in subfertility or infertility. Cyclophosphamide (CY) is a cytotoxic alkylating agent that has been widely used in the treatment of cancer. Recent studies have shown that synthetic resorcinol lipid AMS35AA (3-Heptyl-3,4,6-trimethoxy-3H-isobenzofuran-1-one) may be an important adjuvant chemotherapy that potentiates mutagenic damage and increases apoptosis caused by CY. The present study investigates the action of AMS35AA alone or/in association with CY on testicular function. Animals were divided into four groups: (a) control group: received only water; (b) CY group: received 150 µg/g of CY b.w., i.p.; (c) AMS35AA group: received 10 µg/g of AMS35AA b.w., i.p; and (d) associated group: received 10 µg/g of AMS35AA + 150 µg/g of CY b.w., i.p. Four weeks after the treatment, the results showed that testes weight of CY and associated groups decreased. However, the number of Sertoli cell and Leydig cell per testis was similar in control and treated groups. Our findings provide strong evidence that the AMS35AA alone or in CY association is not toxic to spermatogenesis. The absence of toxicity of AMS35AA supports the view that the resorcinolic lipid could be used associated with CY chemotherapy without causing adverse effects to testes function.

Evaluation of the Antitumor Potential of the Resorcinolic Lipid 3-Heptyl-3,4,6-trimethoxy-3H-isobenzofuran-1-one in Breast Cancer Cells.

BACKGROUND/AIM: In recent years, the search for new anticancer experimental agents derived from natural products or synthetic analogues, such as resorcinolic lipids, has received increased attention. The present study aimed to evaluate the antitumor potential, describe the cell death mechanism and the effects of 3-Heptyl-3,4,6-trimethoxy-3Hisobenzofuran-1-one (AMS35AA) in combination with different chemotherapeutic agents in the MCF-7 cell line. MATERIALS AND METHODS: Analysis of cytotoxic, genotoxic, membrane integrity, cell death and gene expression induced by the compound was performed. RESULTS: The AMS35AA and its association with 5-FU demonstrated reduction of cell viability; increase of cell death; enhancement of genomic damage and accumulation of cells in G2/M phase. CONCLUSION: AMS35AA has potential for breast cancer treatment since it is capable of exerting cytotoxic and cytostatic effects in a breast cell line and also could be an adjuvant in cancer therapy when combined with 5-FU.

Resorcinolic lipid 3-heptyl-3,4,6-trimethoxy-3H-isobenzofuran-1-one is a strategy for melanoma treatment.

AIMS: Previous studies performed by our research group indicated that cytosporone analogues are capable of prevent or repair DNA damages. This work presents the evaluation of the activity of AMS35AA for metastatic murine melanoma cells (B16F10) in experimental model in vitro and, in pre-clinic assay of metastatic melanoma in vivo, using mice lineage C57BL/6. MAIN METHODS: In vitro assays were performed: MTT and comet assay, flow cytometry evaluation, gene expression assay by RT-PCR, qualitative evaluation of cell death using B16F10 cells. In vivo assays: micronucleus and comet assay, splenic phagocytosis, melanoma murine model and histopathological analysis, using mice lineage C57BL/6 (n = 20). KEY FINDINGS: In vitro results performed by MTT assay showed that AMS35AA is cytotoxic for B16F10 cells (p < 0.05). Based on comet assay the genotoxicity of the IC50 was determined (95.83 µg/mL) (p < 0.05). These data were corroborated by flow cytometry analysis after the treatment with AMS35AA, which indicates the cellular death by apoptosis (p < 0.05) and increasing of ATR, p53, p21 and GADD45 gene expressions verified using RT-PCR. With respect to in vivo results, it was observed that AMS35AA did not show genotoxic activity. Data of tumor volume ex vivo indicate reduction of tumor for the treated animals with AMS35AA up to 15.84×, which is superior to Dacarbazina (50 mg/Kg, p.c.; i.p.). SIGNIFICANCE: In summary, the study showed that AMS35AA reveals relevant results regarding to cytotoxicity of B16F10 murine melanoma cells, inducing death by apoptosis via mitochondrial and/or mediated by DNA damages.

In vivo chemotherapeutic insight of a novel isocoumarin (3-hexyl-5,7-dimethoxy-isochromen-1-one): Genotoxicity, cell death induction, leukometry and phagocytic evaluation.

Chemotherapy is one of the major approaches for the treatment of cancer. Therefore, the development of new chemotherapy drugs is an important aspect of medicinal chemistry. Chemotherapeutic agents include isocoumarins, which are privileged structures with potential antitumoral activity. Herein, a new 3-substituted isocoumarin was synthesized from 2-iodo-3,5-dimethoxy-benzoic acid and oct-1-yne in a cross-coupling Sonogashira reaction followed by a copper iodide-catalyzed intramolecular cyclization as key step using MeOH/Et3N as the solvent system. The present study also evaluated the leukometry, phagocytic activity, genotoxic potential and cell death induction of three different doses (5 mg/kg, 10 mg/kg and 20 mg/kg) of this newly synthesized isocoumarin, alone and in combination with the commercial chemotherapeutic agents cyclophosphamide (100 mg/kg) and cisplatin (6 mg/kg) in male Swiss mice. The results suggest that the isocoumarin has genotoxicity and causes cell death. Noteworthy, this new compound can increase splenic phagocytosis and lymphocyte frequency, which are related to immunomodulatory activity. When combined with either cyclophosphamide or cisplatin, chemopreventive activity led to a reduction in the effects of both chemotherapeutic drugs. Thus, the new isocoumarin is not a candidate for chemotherapeutic adjuvant in treatments using cyclophosphamide or cisplatin. Nevertheless, the compound itself is an important prototype for the development of new antitumor drugs.

In vivo chemotherapeutic insight of a novel isocoumarin (3-hexyl-5,7-dimethoxy-isochromen-1-one): Genotoxicity, cell death induction, leukometry and phagocytic evaluation

Abstract Chemotherapy is one of the major approaches for the treatment of cancer. Therefore, the development of new chemotherapy drugs is an important aspect of medicinal chemistry. Chemotherapeutic agents include isocoumarins, which are privileged structures with potential antitumoral activity. Herein, a new 3-substituted isocoumarin was synthesized from 2-iodo-3,5-dimethoxy-benzoic acid and oct-1-yne in a cross-coupling Sonogashira reaction followed by a copper iodide-catalyzed intramolecular cyclization as key step using MeOH/Et3N as the solvent system. The present study also evaluated the leukometry, phagocytic activity, genotoxic potential and cell death induction of three different doses (5 mg/kg, 10 mg/kg and 20 mg/kg) of this newly synthesized isocoumarin, alone and in combination with the commercial chemotherapeutic agents cyclophosphamide (100 mg/kg) and cisplatin (6 mg/kg) in male Swiss mice. The results suggest that the isocoumarin has genotoxicity and causes cell death. Noteworthy, this new compound can increase splenic phagocytosis and lymphocyte frequency, which are related to immunomodulatory activity. When combined with either cyclophosphamide or cisplatin, chemopreventive activity led to a reduction in the effects of both chemotherapeutic drugs. Thus, the new isocoumarin is not a candidate for chemotherapeutic adjuvant in treatments using cyclophosphamide or cisplatin. Nevertheless, the compound itself is an important prototype for the development of new antitumor drugs.

Cardanol: toxicogenetic assessment and its effects when combined with cyclophosphamide.

Cardanol is an effective antioxidant and is a compound with antimutagenic and antitumoral activity. Here, we evaluated the genotoxic and mutagenic potential of saturated side chain cardanol and its effects in combination with cyclophosphamide in preventing DNA damage, apoptosis, and immunomodulation. Swiss mice were treated with cardanol (2.5, 5 and 10 mg/kg) alone or in combination with cyclophosphamide (100 mg/kg). The results showed that cardanol is an effective chemopreventive compound, with damage reduction percentages that ranged from 18.9 to 31.76% in the comet assay and from 45 to 97% in the micronucleus assay. Moreover, cardanol has the ability to reduce the frequency of apoptosis induced by cyclophosphamide. The compound did not show immunomodulatory activity. A final interpretation of the data showed that, despite its chemoprotective capacity, cardanol has a tendency to induce DNA damage. Hence, caution is needed if this compound is used as a chemopreventive agent. Also, this compound is likely not suitable as an adjuvant in chemotherapy treatments that use cyclophosphamide.

A novel cytosporone 3-Heptyl-4,6-dihydroxy-3H-isobenzofuran-1-one: synthesis; toxicological, apoptotic and immunomodulatory properties; and potentiation of mutagenic damage.

BACKGROUND: A large number of studies are attempting to identify alternative products from natural sources or synthesized compounds that effectively interact with cancer cells without causing adverse effects on healthy cells. Resorcinolic lipids are a class of bioactive compounds that possess anticancer activity and are able to interact with the lipid bilayer. Therefore, the objective of this study was to synthesize a novel resorcinolic lipid and test its biological proprieties. METHODS: We aimed to synthesize a novel resorcinolic lipid belonging to the class of cytosporones, AMS049 (3-Heptyl-4,6-dihydroxy-3H-isobenzofuran-1-one) and to evaluate the toxicity of two concentrations of this lipid (7.5 and 10 mg/kg) by determining its genotoxic, mutagenic, immunomodulatory, and apoptotic effects, as well as any biochemical and histopathological alterations in mice treated with cyclophosphamide. The results were analyzed by ANOVA followed by the Tukey test A . level of significance of p < 0.05 was adopted. RESULTS: The new cytosporone AMS049 was synthesized in only three steps and in satisfactory yields. The results indicate that the compound is neither genotoxic nor mutagenic and does not alter biochemical parameters. The histological alterations observed in the liver and kidneys did not compromise the function of these organs. Histology of the spleen suggested immunomodulation, although no changes were observed in splenic phagocytosis or differential blood cell count. The results also show that AMS049 potentiates the mutagenic effect of the chemotherapy drug cyclophosphamide and that the combination induces apoptosis. CONCLUSION: These facts indicate a potential therapeutic application of this novel cytosporone as an important chemotherapeutic adjuvant.

A new synthetic resorcinolic lipid 3-heptyl-3,4,6-trimethoxy-3H-isobenzofuran-1-one: evaluation of toxicology and ability to potentiate the mutagenic and apoptotic effects of cyclophosphamide.

Resorcinolic lipids have important biological actions, including anti-carcinogenic activity. Therefore, we evaluated the mutagenic, genotoxic, immunomodulatory and apoptotic potential and the biochemical and histopathological changes caused by the synthetic resorcinolic lipid 3-Heptyl-3,4,6-trimethoxy-3H-isobenzofuran-1-one, (AMS35AA; 10, 20 and 40 mg/kg) alone or in combination with cyclophosphamide (100 mg/kg) in Swiss mice. The results indicated that AMS35AA is not genotoxic or mutagenic and does not alter liver or kidney histology. However, the compound does cause an increase (p < 0.05) in the levels of glutamic-oxaloacetic transaminase and creatinine and in splenic phagocytosis and liver and kidney apoptosis. When combined with cyclophosphamide, AMS35AA caused increased (p < 0.05) mutagenic damage (although the compound had anti-genotoxic activity), splenic phagocytosis, neutropenia and glutamic-oxaloacetic transaminase and creatinine levels (even in the absence of histological damage) and induced liver and kidney apoptosis. We conclude that this resorcinolic lipid may be an important chemotherapy adjuvant that can potentiate mutagenic damage and increase apoptosis caused by cyclophosphamide without causing adverse effects. In addition, the immunomodulatory activity of the compound should be noted, which counters reductions in lymphocyte number, a primary side effect of cyclophosphamide in cancer therapy.