Comparison of Mitochondrial and Antineoplastic Effects of Amiodarone and Desethylamiodarone in MDA-MB-231 Cancer Line.

Previously, we have demonstrated that amiodarone (AM), a widely used antiarrhythmic drug, and its major metabolite desethylamiodarone (DEA) both affect several mitochondrial processes in isolated heart and liver mitochondria. Also, we have established DEA's antitumor properties in various cancer cell lines and in a rodent metastasis model. In the present study, we compared AM's and DEA's mitochondrial and antineoplastic effects in a human triple-negative breast cancer (TNBC) cell line.

Involvement of Mitochondrial Mechanisms and Cyclooxygenase-2 Activation in the Effect of Desethylamiodarone on 4T1 Triple-Negative Breast Cancer Line.

Novel compounds significantly interfering with the mitochondrial energy production may have therapeutic value in triple-negative breast cancer (TNBC). This criterion is clearly fulfilled by desethylamiodarone (DEA), which is a major metabolite of amiodarone, a widely used antiarrhythmic drug, since the DEA previously demonstrated anti-neoplastic, anti-metastasizing, and direct mitochondrial effects in B16F10 melanoma cells. Additionally, the more than fifty years of clinical experience with amiodarone should answer most of the safety concerns about DEA.

Involvement of Mitochondrial Mechanisms in the Cytostatic Effect of Desethylamiodarone in B16F10 Melanoma Cells.

Previously, we showed that desethylamiodarone (DEA), a major metabolite of the widely used antiarrhythmic drug amiodarone, has direct mitochondrial effects. We hypothesized that these effects account for its observed cytotoxic properties and ability to limit in vivo metastasis. Accordingly, we examined DEA's rapid (3-12 h) cytotoxicity and its early (3-6 h) effects on various mitochondrial processes in B16F10 melanoma cells.

Amiodarone's major metabolite, desethylamiodarone inhibits proliferation of B16-F10 melanoma cells and limits lung metastasis formation in an in vivo experimental model.

Previously, we demonstrated the in vitro anti-tumor effects of desethylamiodarone (DEA) in bladder and cervix cancer cell lines. In the present study, we intended to establish its potentiality in B16-F10 metastatic melanoma cells in vitro and in vivo. We assessed cell proliferation, apoptosis and cell cycle by using sulforhodamine B assay, Muse™ Annexin V & Dead Cell and Muse® Cell Cycle assays, respectively.

Amiodarone's major metabolite, desethylamiodarone, induces apoptosis in human cervical cancer cells.

Previously, we found that desethylamiodarone (DEA) may have therapeutic potentiality in bladder cancer. In this study, we determined its effects on human cervical cancer cells (HeLa). Cell viability was evaluated by Muse Cell Count & Viability Assay; cell apoptosis was detected by Muse Annexin V & Dead Cell Assay.

Desethylamiodarone-A metabolite of amiodarone-Induces apoptosis on T24 human bladder cancer cells via multiple pathways.

Bladder cancer (BC) is a common malignancy of the urinary tract that has a higher frequency in men than in women. Cytostatic resistance and metastasis formation are significant risk factors in BC therapy; therefore, there is great interest in overcoming drug resistance and in initiating research for novel chemotherapeutic approaches. Here, we suggest that desethylamiodarone (DEA)-a metabolite of amiodarone-may have cytostatic potential.

Modification of Acute and Chronic Liver Damage by Thiazolidine Compounds.

As high sulfhydril levels were shown to reduce the action of agents causing tissueinjury, increasing glutathion concentrations may have cytoprotective potential. In this study the hepatoprotective effects of several derivatives of 4carboxy5,5dimethyl thiazolidine, a modulator of glutathion metabolism were studied in rat liver damaged with CCl4. It was found that 4(S) carboxy 5,5dimethyl2 (5'nitro2furyl) thiazolidine (dimethylthiazolidinenitrofuran: DTNF) had the most significant hepatoprotective action; therefore it was subjected to detailed investigation in various models for acute and chronic liver injury.

A new cyclitol derivative influences inositol metabolism in Neurospora crassa.

Cyclitol derivatives have been synthesized and screened for growth inhibitory effect upon prokaryotic and eukaryotic organisms. One derivative, (2S,3R,5R)-3-azido-2-benzoyloxy-5-hydroxycyclohexanone, was studied in detail: it has no effect upon bacteria, but it is inhibitory to Neurospora crassa. In Neurospora crassa it increased the amount of myo-inositol-1-phosphate synthase and inhibited the activity of myo-inositol-monophosphatase.

13C NMR study of actinoidins: carbohydrate moieties and their glycosidic linkages.

The configuration of the glycosidic linkages and the conformation of the carbohydrate moieties in the molecules of the glycopeptide-type antibiotics actinoidins A and B (1a, 1b) have been determined by means of two-dimensional 13C/1H correlation NMR technique and with the application of model compounds 2-4.

Synthesis of hypolipidemic silybin analog 3',4'-ethylenedioxyflavonoids.

For pharmacological investigation various types of silybin analogues have been synthesized. According to the results of preliminary tests, many of the prepared benzodioxane analogues of chalcones, chalcone epoxides, isoflavones, flavanones and aurones possessed hypolipidemic activity.

Synthesis, antibacterial and antifungal activity of 4-hydroxycoumarin derivatives, analogues of novobiocin.

3-Acylamino-, -arylsulfonylamino-, -(N'-arylureido)-, -arylideneamino- and -arylcarbamoyl-4-hydroxycoumarins have been synthesized and tested for antibacterial and antifungal activity. 3-Arylcarbamoyl-4-hydroxycoumarins have been shown to possess significant activity against Gram-positive bacteria; 3-acylamino-4-hydroxycoumarins have moderate antibacterial and antifungal effects whereas the additional compounds are inactive.

High performance liquid chromatography (HPLC) of antibiotics of vancomycin type. Comparative studies.

Comparative HPLC examination of seven antibiotics of vancomycin type has been undertaken. Investigation has shown that on column I in eluent system B, ristomycin A (ristocetin A) can be not only separated from vancomycin, but both antibiotics can be quantitatively determined. Under these conditions the lowest detectable quantities of the individual antibiotics have been also stated.

Structural investigation of the antibiotic ristomycin A. 13C-NMR spectral analysis of the interglycosidic linkages of the heterotetrasaccharide side-chain.

By 13C-NMR studies on Ia, IIa, IIb and IVa obtained by the chemical degradation of ristomycin A and on several synthetic model compounds it has been proved that an O-beta-D-arabinopyranosyl-(1 leads to 2)-O-alpha-D-mannopyranosyl-(1 leads to 2)-O-[alpha-L-rhamnopyranosyl-(1 leads to 6)]-D-glucopyranosyl heterotetrasaccharide moiety is connected to the aglycone of the antibiotic.

[Study of the antibiotic parvulomycin. The isolation of alpha,alpha-trehalose and L-glutamic acid].

A non-reducing disugar and amino acid were isolated in the studies on the structure of parvulomycin. The acid hydrolysis of the disugar revealed the presence of 2 moles of D-glucose. Acetylation of the disugar resulted in formation of octa-O-acetyl-alpha,alpha-tregalose, saponification of which resulted in formation of alpha,alpha-tregalose.

Study of the antitumoral activity of S-carbamoyl-L-cysteine derivatives in animal experiments.

The antitumoral activity of three amino acid derivatives, S-carbamoyl-L-cysteine, S-ethyl-carbamoyl-L-cysteine, and S-chloroethyl-carbamoyl-L-cysteine, was studied. The ethyl and chloroethyl derivatives had a pronounced curative effect on certain animal tumors. It is interesting in the case of S-carbamoyl-L-cysteine that N-ethylization of the substance resulted in increased chemotherapeutic effectivity with no simultaneous change of the toxicity.

Structural investigation of the antibiotic ristomycin A. Synthesis of ristobiose and ristotriose.

Proof is given by synthesis confirming the structure of ristobiose as 2-O-alpha-D-mannopyranosyl-D-glucose (IV) and ristotriose as O-alpha-L-rhamnopyranosyl (1 leads to 6)-O-[alpha-D-mannopyranosyl (1 leads to 2)]-D-glucose (X) which are obtained from ristomycin A upon mild acid hydrolysis. Both oligosaccharides, IV and X, have been detected for the first time as the components of an antibiotic.

[Structure of the carbohydrate moiety of actinoidins A and B].

The structure of the carbohydrate moiety of actinoidins A and B was found with partial acid hydrolysis (metanolysis) of the antibiotics and their methyl derivatives and the method of periodate oxidation. Actinoidins A and B had 3 carbohydrate branches presented by the residues of monosugars of D-mannopyranose and 2, 3, 6-tridesoxy-3-amino-4-O-methyl-L-arabinopyranose(L-actinosamine) and disaccharide of 2-O-(2, 3, 6-tridesoxy-3-amino-L-arabinopyranosyl)-D-glucopyranose.