Synthesis and antitumor properties of 3'-desamino-3'-dimethylformamidinorubomycin

Interaction of rubomycin (daunorubicin) chlorhydrate with dimethylformamidine diethyl acetal yielded 3'-desamino-3'dimethylformamidinorubomycin chlorhydrate (DFR). Comparative antitumor activity of DFR and rubomycin was studied on mice with respect to ascitic lymphadenosis NK/Ly and Ehrlich carcinoma, hemocytoblastosis La, leukemia P-388 and two solid tumors i. e. lymphosarcoma LIO-I and sarcoma 180. The highest antitumor effect of DFR was observed in the mice with Ehrlich carcinoma and lymphadenosis NK/Ly after the drug intravenous administration for 4 times. By selectivity of the antitumor effect DFR was inferior to rubomycin with respect to lymphosarcoma LIO-I and sarcoma 180. It was shown that the antileukemic activity of DFR and rubomycin with respect to hemocytoblastosis La was practically the same. In the experiments with leukemia P-388 DFR was inferior to rubomycin.     

Synthesis and antitumor activity of new D-galactose-containing derivatives of doxorubicin

A general scheme of synthesis of antibiotic doxorubicin derivatives is based on the 13-dimethyl ketal of 14-bromodaunorubicin (4). The interaction of 4 with melibiose (5), lactose (6), 3-methoxy-4-O-(2,3,4,6-tetra-O-acetyl-beta-D-galactopyranosyl)-4-oxybenzaldehyde (12) or 4-O-(2,3,4,6-tetra-O-acetyl-beta-D-galactopyranosyl)-4-oxybenzaldehyde (13) by reductive alkylation followed by hydrolysis of the corresponding intermediate bromoketals produced 3'-N-[alpha-D-galactopyranosyl-(1-->6)-O-1-deoxy-D-glucit-1-yl]doxorubicin (7), 3'-N-[beta-D-galactopyranosyl-(1-->4)-O-1-deoxy-D-glucit-1-yl]doxorubicin (8), 3'-N-[3"-methoxy-4"-O-(beta-D-galactopyranosyl)-4"-oxybenzyl]doxorubicin (16), and 3'-N-[4"-O-(beta-D-galactopyranosyl)-4"-oxybenzyl]doxorubicin (17). Cytotoxic and antitumor activity of the synthesized drug candidates compared to the parent doxorubicin was studied using various experimental models, in particular, on mice bearing lymphocyte leukemia P-388 at single and multiple i.v. injection regimens.     

Synthesis and preliminary antitumor activity evaluation of a DHA and doxorubicin conjugate

A conjugate of DHA and doxorubicin (DHA-Dox) was synthesized, and its antitumor activity was evaluated in vitro against L1210 leukemia cells and in experimental animal tumor models including L1210 leukemia and B16 melanoma. DHA-Dox showed a greatly improved antitumor efficacy compared to free doxorubicin.     

Synthesis and antitumor properties of carminomycin 13-cyclohexylidenhydrazone

Carminomycin 13-cyclohexylidenhydrazone (CCH) was prepared by interaction of carminomycin 13-hydrazone with cyclohexane. The antiblastomic properties of CCH were studied on mice with transplantable tumors. The preparation was administered intravenously or orally. The studies showed a high antitumor activity of CCH. When CCH was administered intravenously to mice with lymphosarcoma LIO-1, the antitumor effect selectivity of it was practically equal to that of carminomycin. When used in doses equivalent by their toxicity to those of carminomycin, CCH had practically the same inhibitory effect on sarcoma 180 as carminomycin. When used orally in doses equivalent by their toxicity to those of carminomycin, CCH was more effective than carminomycin in treatment of mice with lymphosarcoma LIO-1, sarcoma 180 and lymphadenosis NK/Ly.     

Synthesis and antitumor activity of 3'-C-methyl-daunorubicin

Reaction of 1,5-anhydro-4-O-benzoyl-2,3,6-trideoxy-3-C-methyl-3-trifluoro-acetami no-L-lyxo-hex-1-enitol with daunomycinone in the presence of anhydrous toluene-p-sulfonic acid in benzene, followed by removal of the N- and O-protecting groups under mild conditions, gave 3'-C-methyldaunorubicin. The antitumor activity of the new anthracycline glycoside has been evaluated.     

New conjugates of antitumor antibiotic doxorubicin with water-soluble galactomannan: Synthesis and biological activity

New water-soluble conjugates in the form of Schiff bases (DGM-1 and DGM-2) were prepared by the interaction of water-soluble periodate-oxidized galactomannan with doxorubicin or N-(L-lysyl)doxorubicin, respectively. The water-soluble galactomannan (DAVANAT®, a commercial product of Pro-Pharmaceuticals company) was obtained by partial acidic hydrolysis of high-molecular-mass galactomannan from Cyamopsis tetragonoloba (guar gum) seeds. The conjugate stability was studied in aqueous solutions. The DGM-1 anti-proliferative activity was comparable with that of doxorubicin on three models: cell lines of murine melanoma B16-F1 and human breast cancer MCF-7 (HTB-22) and human colon cancer HT-29 (HTB-38). DGM-2 was poorly active in all the three tests. DGM-1 can thus be regarded as a high-molecular-mass depot form of doxorubicin.     

Synthesis and properties of star-comb polymers and their doxorubicin conjugates

We describe a six-step synthesis to water-soluble doxorubicin (DOX)-loaded biodegradable PEGylated star-comb polymers with favorable pharmaceutical properties by atom transfer radical polymerization (ATRP) starting with a commercially available tripentaerythritol carrying eight reactive sites. The low polydispersity polymers degrade in a stepwise manner into lower molecular weight (MW) fragments by 15 days at 37 °C at either pH 5.0 or pH 7.4. The half-life of the star-comb polymers in blood is dependent upon the molecular weight; the 44 kDa star-comb has a t(1/2, β) of 30.5 ± 2.1 h, which is not significantly changed (28.6 ± 2.7 h) when 6.6 wt % of DOX is attached to it via a pH-sensitive hydrazone linker. The star-comb polymers have low accumulation in organs but a high accumulation in C26 flank tumors implanted in Balb/C mice. The hydrodynamic diameter of polymer-DOX conjugates measured by dynamic light scattering increases from 8 to 35 to 41 nm as the loading is increased from 6.6 to 8.4 to 10.2 wt %. Although there is no significant difference in the t(1/2, β) or in the accumulation of polymer-DOX in C-26 tumors, the uptake of polymer in the spleen is significantly higher for polymers with DOX loadings greater than 6.6 wt %. Polymer accumulation in other vital organs is independent of the DOX loading. The facile synthesis, biodegradability, long circulation time, and high tumor accumulation of the attached drug suggests that the water-soluble star-comb polymers have promise in therapeutic applications.     

Synthesis and antitumor properties of the myelopeptide MP-1

The bone marrow-derived peptide Phe-Leu-Gly-Phe-Pro-Thr (MP-1) has been synthesized by the classical methods of peptide chemistry in solution, and its antitumor properties have been studied. It has been shown that MP-1 enhances the efficacy of the cytostatic therapy of lympholeukosis P388, increases the latent period of the growth of P388 tumors implanted in irradiated mice, and reduces the recurrence of the breast adenocarcinoma Ca-755 in mice after the surgery.     

Synthesis of heterocycle-based analogs of resveratrol and their antitumor and vasorelaxing properties

New resveratrol (RES) analogs were developed by replacing the aromatic ‘core’ of our initial naphthalene-based RES analogs with pseudo-heterocyclic (salicylaldoxime) or heterocyclic (benzofuran, quinoline, and benzothiazole) scaffolds. The resulting analogs were tested for their antiproliferative and vasorelaxing effect, two typical properties shown by RES. Some of the new compounds confirmed strong antiproliferative activities, comparable to that previously found with the most active naphthalene-based analog. In particular, 3-(3,5-dihydroxyphenyl)-7-hydroxyquinoline exhibited the most potent antiproliferative effect (IC₅₀ = 17.4 μM). In vascular assays, the highest levels of potency (pIC₅₀ = 4.92) and efficacy (E_max = 88.2%) were obtained with 2-(3,5-dihydroxyphenyl)-6-hydroxybenzothiazole. A conformational analysis of these compounds indicated that the antiproliferative activity on MDA-MB-231 cancer cells can be correlated to a common sterical profile of the most active compounds and, in particular, to the spatial arrangement of the three phenolic groups. Furthermore, the vasorelaxing properties showed a good correlation with the electronic properties measured through the electrostatic molecular potential (ESP).     

Synthesis and antitumor activities of 3-modified 2-methoxyestradiol analogs

The syntheses of 2-methoxyestradiol analogs with modifications at the 3-position are described. The analogs were assessed for their antiproliferative, antiangiogenic, and estrogenic activities. Several lead substituents were identified with similar or improved antitumor activities and reduced metabolic liability compared to 2-methoxyestradiol.     

Synthesis and antitumor properties of 2,5-bis(3'-indolyl)thiophenes: analogues of marine alkaloid nortopsentin

A series of 11 bis-indolylthiophenes of type 8-10 were obtained by cyclization of diketones 4 and 7 using Lawesson's reagent. Derivatives 8c, 9c, 9d, and 10c were selected to be evaluated in the full panel of about 60 human tumor cell lines derived from nine human cancer cell types and showed antiproliferative activity generally in the micromolar range. The most sensitive cell lines were: CCRF-CEM, MOLT-4, HL60 (TB), and RPMI-8226 of the leukemia subpanel, HT29 and HCC-2998 cell lines of the colon sub-panel, NCI-H522 of the non-small cell lung cancer sub-panel, LOX IMVI of the melanoma sub-panel, and UO-31 of the renal cancer sub-panel.     

Synthesis, characterization and antitumor properties of some metal complexes of 3- and 5-substituted salicylaldehyde 2-pyridinylhydrazones

Complexes of Mn(II), Fe(II), Co(II), Ni(II), Cu(II), Zn(II), and Pt(II) with 3- and 5-substituted salicylaldehyde 2-pyridinylhydrazones (XSPH, X = H, 3-NO2, 3-CH3O, 5-Br, 5-Cl, 5-CH3, or 5-NO2) have been prepared and characterized by elemental analysis, conductance measurements, magnetic moments (300-78 K), and spectral studies. On the basis of these studies a monomeric, high-spin, distorted octahedral structure for Mn(XSPH)2 and Fe(XSPH)2, a dimeric, high-spin, five-coordinate structure for Co(XSBH)Cl, a dimeric, low-spin, five-coordinate structure for Ni(XSPH)Cl and Zn(XSPH)(OAc), and a square-planar structure for M(XSPH)Cl.H2O (M = Cu(II) or Pt(II] complexes are suggested. The polycrystalline ESR spectra of Cu(II) complexes are isotropic and suggest dx2-y2 ground state in square-planar stereochemistry. M?ssbauer spectral results indicate distorted octahedral structure for iron(II) complexes. All the metal(II) complexes have been screened for their antitumor activity against P388 lymphocytic leukemia test system in mice and have been found to possess no significant activity at the dosages used.     

Synthesis and properties of new substituted 1,2,4-triazoles: potential antitumor agents

Cycloaddition of the reactive intermediates 4 with 1-(cyanomethyl)benzotriazole (5) and its N-2 isomer 9 furnished, after spontaneous rearrangements, the 1,2,4-triazole derivatives 8 and 10. Analogously, reaction of 4 with ethyl cyanoacetate lead to the 1,3,5-trisubstituted 1,2,4-triazoles 12, which gave on treatment with hydrazine the corresponding hydrazides 13. Treatment of 13d with galactose or phenyl isothiocayanate gave the 1-D-galactose-acylhydrazone 14 and the 1,2,4-triazole derivative 15, respectively. Compounds 8c; 10b,c; 13a,c and 14 were selected for the antitumor screening, whereby 8c, 13a, and 13c showed remarkable activity against leukemia, ovarian, renal and lung cancers (8c with Gl(50) of 0.70 microM, 0.07 microM against leukemia (CCRF-CEM and RPMI-8226), 0.02 microM against ovarian (OVCAR-3) and 0.60 microM against renal (CARKI-1) and lung cancers, respectively).     

Synthesis, characterization, antitumor activity of pluronic mimicking copolymer micelles conjugated with doxorubicin via acid-cleavable linkage

Pluronic mimicking poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) triblock copolymer having multiple hydroxyl groups in the PPO middle segment (core-functionalized Pluronic: CF-PLU) was synthesized for conjugation of doxorubicin (DOX). DOX was conjugated on the multiple hydroxyl groups of CF-PLU via an acid-labile hydrazone linkage (CF-PLU-DOX). In aqueous solution, CF-PLU-DOX copolymers self-assembled to form a core/shell-type micelle structure consisting of a hydrophobic DOX-conjugated PPO core and a hydrophilic PEO shell layer. The conjugated DOX from CF-PLU-DOX micelles was released out more rapidly at pH 5 than pH 7.4, indicating that the hydrazone linkage was cleaved under acidic condition. CF-PLU-DOX micelles exhibited greatly enhanced cytotoxicity for MCF-7 human breast cancer cells compared to naked DOX, while CF-PLU copolymer itself showed extremely low cytotoxicity. Flow cytometry analysis revealed that the extent of cellular uptake for CF-PLU-DOX micelles was greater than free DOX. Confocal image analysis also showed that CF-PLU-DOX micelles had a quite different intracellular distribution profile from free DOX. CF-PLU-DOX micelles were mainly distributed in the cytoplasm, endosomal/lysosomal vesicles, and nucleus, while free DOX was localized mainly within the nucleus, suggesting that CF-PLU-DOX micellar formulation might be advantageously used for overcoming the multidrug resistance (MDR) effect, which gradually develops in many tumor cells during repeated drug administration.     

Synergistic antitumor effects of rhein and doxorubicin in hepatocellular carcinoma cells

The aim of this study was to investigate the synergistic antitumor activity of rhein and doxorubicin (DOX) and to elucidate the underlying mechanisms in hepatocellular SMMC-7721 and HepG2 cells. Cell growth curves, caspase-3 activity, and intracellular DOX accumulation were observed using an IncuCyte real-time video imaging system. Combination index was used to calculate synergistic potential of rhein and DOX. Cell apoptosis was detected by the Annexin V-FITC/PI apoptosis kit. Lactate dehydrogenase and adenosine triphosphate (ATP) levels were assessed using an assay kit. Oxygen consumption rates (OCR) and extracellular acidification rates were assessed by the Seahorse XFe96 Extracellular Flux Analyzer. Mitochondrial inner membrane potential (ΔΨm) was monitored with JC-1 fluorescence. Western blot analysis was used to detect the level of P-glycoprotein. Synergistic antiproliferative and proapoptotic effects were exerted by the combination of rhein at 10 μM and DOX at 2 μM in SMMC-7721 and HepG2 cells. Rhein could influenced the accumulation of DOX in both cells, which was associated with remarkably decreased mitochondrial energy metabolism and ATP levels. Rhein could reduce ΔΨm in both cells. mPTP, opener atractyloside (ATR) could accelerate the loss of ΔΨm, and further suppress the OCR induced by rhein. In contrast, the mPTP blocker cyclosporin A (Cs A) inhibited the loss of ΔΨm and the OCR induced by rhein. Our data indicate that a decline in mitochondrial energy metabolism was responsible for the synergistic antitumor effects of rhein and DOX in hepatocellular carcinoma cells. Reduction of ΔΨm and opening of mPTP inhibited the exchange of ATP/adenosine diphosphate between mitochondrial matrix and cytoplasm is the important mechanism.     

Synthesis and antitumor activity of 2'-bromo- and 2'-chloro-3'-acetoxy-3'-deaminodaunorubicin analogs

Bromination of 3,4-di-O-acetyl-L-rhamnal (7) and subsequent glycosidic coupling under Koenigs-Knorr conditions with daunomycinone gave a mixture of three compounds having the beta-L-gluco (10), alpha-L-gluco (11), and alpha-L-manno (12) configurations. Analogous bromination of 3,4-di-O-acetyl-L-fucal (13) followed by coupling with daunomycinone gave a mixture of three glycosides having the beta-L-galacto (16), alpha-L-galacto (17), and alpha-L-talo (18) configurations. Chlorination of 7 and coupling with daunomycinone in the presence of silver triflate gave products having the alpha-L-gluco (21) and alpha-L-manno (22) configurations, whereas 13, under similar conditions, gave only one stereoisomeric product, that having the alpha-L-galacto (24) configuration. Compounds 12 and 22 showed high in vivo activity in the P-388 lymphocytic leukemia assay.     

Synthesis of antitumor 6-alkylidenepenicillanate sulfones and related 3-alkylidene-2-azetidinones

6-alkylidenepenicillanate sulfoxides and sulfones were synthesized on the base of 6-oxopenicillanate esters. The targeted splitting of their thiazolidine ring led to the formation of 3-alkylidene substituted 4-heteryldithio and 4-methylsulfonyl azetidin-2-ones. Some of mono and bicyclic beta-lactams revealed potent cytotoxic properties towards monolayer tumor cells in <10-microM concentrations.     

Synthesis and antitumor activity of fluorocyclopentenyl-pyrimidines

Synthesis of fluorocyclopentenyl pyrimidine nucleosides 6-9 was enantiopurely accomplished employing oxidative rearrangement, RCM reaction and electrophilic fluorination starting from d-ribose. Cytosine analog 8 was found to exhibit significant anticancer activity in various human tumor cell lines.     

Production and antitumor properties of carminazone

Karminazon (13-benzoylhydrazon) was prepared by condensation of karminomycin with benzoylhydrazine. In its intravenous use in the treatment of mice with lymphosarcoma L10-1 karminazon was less toxic and had lower antitumor activity than karminomycin. Karminazon had a lower selective antitumor activity with respect to lymphosarcoma than karminomycin.     

Synthesis and antitumor activity of cholest-4 alpha-methyl-7-en-3beta-ol derivatives

Cholest-4 alpha-methyl-7-en-3beta-ol (1) has potent inhibitory activity against pc 12 tumor with 0.5043 ratio (10 microg/mL). This paper describes a series of structural modification of this compound, which focus on 3beta-hydroxyl group and 7(8)-double bond. The synthesized derivatives of 1 were tested for human cancer cell lines including colon cancer (HCT-8), liver cancer (BEL-7402) and nasopharyngeal cancer (KB) cells. The results showed that cholest-4 alpha-methyl-8-en-3beta,7 alpha-diol 6a inhibits KB cell significantly with IC(50) 1.32 x 10(-9)microg/mL. In addition, the cytotoxic properties of this compound against HCT-8 and BEL-7402 are excellent with IC(50) 1.2 microg/mL.