Roberto da Silva Gomes

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.

4-Aminoantipyrine reduces toxic and genotoxic effects of doxorubicin, cisplatin, and cyclophosphamide in male mice.

The analgesic drug dipyrone is used to treat side effects (including pain and fever) of cancer chemotherapeutic agents. Dipyrone is metabolized to 4-aminoantipyrine (4-AA), a PGE2-dependent blocker and inhibitor of cyclooxygenase (COX). We evaluated the genotoxic, mutagenic, apoptotic, and immunomodulatory activities of 4-AA in vivo and the effects of its combination with the antineoplastic drugs doxorubicin, cisplatin, and cyclophosphamide. 4-AA did not cause genotoxic/mutagenic damage, splenic phagocytosis, or leukocyte alterations. However, when combined with the antineoplastic agents, 4-AA decreased their genotoxic, mutagenic, apoptotic, and phagocytic effects. These results suggest that 4-AA might interfere with DNA damage-mediated chemotherapy.

SYNTHESIS AND EVALUATION OF OCTOCRYLENE-INSPIRED COMPOUNDS FOR UV-FILTER ACTIVITY

Octocrylene (2-ethylhexyl 2-cyano-3,3-diphenyl-2-propenoate) is present in several sunscreens and is known to work synergistically with UV filters. We prepared eight octocrylene-related compounds to test their photoprotective activities by measuring diffuse transmittance. The compounds had varied photoprotection profiles, with Sun Protection Factors (SPF) ranging from 1 to 5 and UVA Protection Factors (UVAPF) ranging from 1 to 8. Compounds 4, 5, and 7 showed the best protection against UVB sunrays, while compounds 5, 6, and 7 presented the best results for protection from UVA, so compound 7 had the most balanced protection overall. Results for compounds 4, 8, and 9 are reported for the first time in the literature.

New Bis copper complex ((Z) -4 - ((4-chlorophenyl) amino) -4-oxobut-2-enoyl) oxy): Cytotoxicity in 4T1 cells and their toxicogenic potential in Swiss mice

&NA; Copper (II) complexes are promising in the development of new synthetic models for cancer treatment. In this context, we synthesized a new copper complex containing the pharmacophore group 1,4‐dioxo‐2‐butenyl, the Bis(((Z)‐4‐((4‐chlorophenyl) amino)‐4‐oxobut‐2‐enoyl)oxy) copper compound and we evaluated its antitumor activity in 4 T1 murine mammary adenocarcinoma cells and their toxicogenic effect in Swiss mice. The compound demonstrated cytotoxicity and genotoxicity to 4 T1 cells, and after cell cycle arrest in G1, which occurred by the increase in ATM and p21 expression, it induced the cells to apoptosis by increasing BAX and caspase‐7. In vivo the compound was genotoxic in mice but did not show permanent damage, observed by the absence of increased micronucleus frequency, and did not induce changes in the biometric parameters of the animals. These results indicate that the new copper complex, described firstly in this work, presents therapeutic potential for breast cancer. Graphical abstract Figure. No caption available. HighlightsThe RC1 compound is cytotoxic to 4T1 murine mammary adenocarcinoma cells.RC1 induces arrest in the G1 phase increasing the expression of ATM and p21.RC1 induces apoptosis increasing BAX and Caspase‐7 genes, and inhibition of BCL‐2.RC1 in vivo unchanged biometric parameters and is less genotoxic than cisplatin.The RC1 compound has therapeutic potential for breast cancer.

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 &mgr;g/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. Graphical abstract Figure. No caption available.

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.

1H and 13C NMR analysis of 2‐acetamido‐3‐mercapto‐3‐methyl‐N‐aryl‐butanamides and 2‐acetamido‐3‐methyl‐3‐nitrososulfanyl‐N‐aryl‐butanamide derivatives

The complete assignment of the 1H and 13C NMR spectra of various 2‐acetamido‐3‐mercapto‐3‐methyl‐N‐aryl‐butanamides and 2‐acetamide‐3‐methyl‐3‐nitrososulfanyl‐N‐aryl‐butanamides with p‐methoxy, o‐chloro and m‐chloro substituents is reported. Copyright

Development of new chiral auxiliary from the Diels-Alder adduct endo-tricyclo[6.2.1.02,7] undeca-4 ,9-dien-3 ,6-dione

Stereochemistry control is very important in organic synthesis and it is a basic challenge in asymmetric synthesis. An approach widely used is making use of chiral auxiliary compounds. In this work it is showed the synthesis of highly optically pure rigid polycyclic compounds from the Diels-Alder adduct 1 . Compounds 1 - 3 were prepared as described by Ito et. al. [1]. The alcohol (-)- 3 was obtained by biotransformation of diketone 2 with Mucor ramosissimus, e.e.>99% (60%). The polycyclic halides 4 - 6 were synthesized (60-97%) after treatment of alcohol (-)- 3 with NBS, NIS and, NCS in dichloromethane, respectively. Compound 7 was prepared by reaction with p-toluenesulfonic acid, whilst 8 was prepared by treatment of (-)- 3 with m-chloroperbenzoic acid. The strained polycylic alcohols 9 - 13 will be achieved by reduction of ketones 4 - 8 with NaBH 4 . All compounds were identified by 1 H and 13 C NMR spectroscopy. Due to intrinsic rigidity of the synthesized polycyclic, they could be of use as chiral auxiliary agents. Prochiral substrates can be readily attached by many ways to C-3 or through hydroxyl group found in compounds 8 - 13 . The stereo-dirigent potential of these polycyclic can also be increased by directly or indirectly introduction of many groups at position C-3, or at adjacent positions to carbonyl or hydroxyl at C-3 and C-10.