Synthesis and antitumor evaluation of benzoylphenylurea analogs

Novel series of benzoylphenylurea analogs 7-10 were prepared and evaluated for in vitro cytotoxic activity against a panel of eight different human cancer cell lines. A very interesting inhibition profile against BxPC3, Mia-Paca, and Hep2 cells with compound 10 has been observed. Compounds 8 and 9 showed the significant cytotoxicity in Hep2 cells. All cell lines were resistant to compound 7.     

Synthesis of the A,B-ring-truncated OSW saponin analogs and their antitumor activities

The A,B-ring-truncated OSW saponin analogs (1, 18a, and 18b) were synthesized. These greatly simplified trans-hydrindane disaccharides retained considerable inhibitory activity against the growth of HeLa and Jurkat T cells (IC(50)=0.8-21.1 microM).     

Synthesis of OSW-1 analogs with modified side chains and their antitumor activities

Four analogs of OSW-1 (1-4) with modified side chains on the steroidal skeleton were synthesized following modification of our previous route for the total synthesis of OSW-1. Testing of the analogs against growth of tumor cells demonstrated that the 22-one function and the full length of the side chain of OSW-1 were not required for the antitumor action of OSW-1.     

Synthesis and antitumor activity of simplified ecteinascidin-saframycin analogs

Two series of simplified analogs of the ecteinascidin-saframycin type alkaloids were prepared from l-DOPA. Their in vitro antitumor activity was tested against three human cancer cell lines (HCT-8 colon carcinoma, Bel-7402 liver carcinoma, and BGC-823 gastric carcinoma). Among these compounds, the ester analogs have stronger activities than those of amide analogs in general. Among them, 1-naphthalene carboxylate ester analog 31 has the strongest activity against BGC-823 cells.     

Synthesis and antitumor evaluation of methyl spongoate analogs

A series of novel methyl spongoate (1) analogs has been synthesized and evaluated for their in vitro cytotoxic properties. It was found that the nature of the C-20 side chain had significant effects on their bioactivities and some analogs showed higher cytotoxicity than 1 against A549, HCT-116, HepG2, SW-1990, MCF-7 and NCI-H460 tumor cell lines. The pharmacological results confirmed that the α,β-unsaturated carbonyl moiety, a Michael acceptor in ring A, plays a pivotal role in the cytotoxic effect of these derivatives. The compiled pharmacological data may be useful for the design of novel analogous anticancer drugs.     

Synthesis and antitumor activity of amine analogs of irofulven

Acylfulvenes, a class of semisynthetic analogs of Illudin S, show high toxicity toward prostate cancer cells. Here we probe the effect of changes in hydrophilic character of the analogs.     

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 of new camptothecin analogs with improved antitumor activities

Novel hexacyclic camptothecin analogs containing cyclic amidine, urea, or thiourea moiety were designed and synthesized based on the proposed 3D-structure of the topoisomerase I (Topo I)/DNA/camptothecin ternary complex. The analogs were prepared from 9-nitrocamptothecin via 7,9-diaminocamptothecin derivatives as a key intermediate. Among them, 7c exhibited in vivo antitumor activities superior to CPT-11 in human cancer xenograft models in mice at their maximum tolerated doses though its in vitro antiproliferative activity was comparable to SN-38 against corresponding cell lines.     

Synthesis and properties of acyclic analogs of ribavirin

Acyclic analogues of ribavirine, viz. 1-(1-hydroxy-4-oxahex-3-yl)-, 1-(1-chloro-4-oxahex-3-yl)-, 1-(1,2-dihydroxy-4-oxahex-3-yl)-, 1-(1,6-dihydroxy-4-oxahex-3-yl)-, 1-(1-chloro-6-hydroxy-4-oxahex-3-yl)-, and 1-(1,2,6-trihydroxy-4-oxahex-3-yl)-1,2,4-triazole-3-carboxamide, with the C3'-C4' bond of the furanose ring cleaved, have been prepared by condensation of trimethylsilyl derivatives of 3-ethoxycarbonyl-1,2,4-triazole with alkylating agents in the presence of SnCl4 followed by treatment with methanolic ammonia. Convenient methods for synthesis of the alkylating agents were elaborated.     

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 new analogs of anthracycline antibiotics modified by aglycon

Anthracycline antibiotics widely used, along with their semisynthetic analogues, in human cancer chemotherapy, are O-glycosides having as aglycon 7,8,9,10-tetrahydronaphtacenequinone-5,10-with some hydroxy groups, a side chain at C-9 and sugar(s) residues, usually at C-7. The review includes the most important studies on the chemical modification of the aglycon moiety of daunorubicin, doxorubicin and carminomycin during last ten years. Activity of the compounds on experimental tumours is described and their structure-activity relationship is discussed.     

Synthesis of monomethylated dioscin derivatives and their antitumor activities

All possible eight monomethylated dioscin derivatives (1-8) were synthesized. Their inhibitory activities against P388 and A-549 cells were determined, and the results indicate that six of the eight hydroxyls of dioscin are the 'key polar groupings' for tumor inhibitory activities.     

Evaluation of antitumor properties of novel saframycin analogs in vitro and in vivo

Novel analogs of (-)-saframycin A are described. The analogs are shown to be potent inhibitors of the in vitro growth of several tumor cells in a broad panel and promising as leads for further optimization. The first in vivo studies in a solid tumor model (HCT-116) reveal potent antitumor activity with associated toxicity of daily administration.     

In Vitro evaluation of the cytotoxic and anti-proliferative properties of resveratrol and several of its analogs

Resveratrol (RES), a component of red wine, possesses anti-inflammatory properties. The studies described in the present work were aimed at evaluating the potential for RES and related stilbene analogs (piceatannol, PIC; pterostilbene, TPS; trans-stilbene, TS; and trans-stilbene oxide, TSO) to exhibit toxicity towards RAW 264.7 mouse macrophages. The effect of TS, TSO, RES and TPS on RAW 264.7 macrophage viability was determined by two standard methods: (a) the MTT assay and (b) the trypan blue dye exclusion test. Whereas macrophages were more sensitive to PIC (LC_{50 trypan} ∼ 1.3 μM) and to TPS (LC_{50 trypan} ∼ 4.0 μM and LC_{50 MTT} ∼ 8.3 μM) than to RES (LC_{50 trypan} ∼ 8.9 μM and LC_{50 MTT} ∼ 29.0 μM), they were relatively resistant to TSO (LC_{50 trypan} ∼ 61.0 μM and LC_{50 MTT} > 100 μM) and to TS (LC_{50 trypan} ≥ 5.0 μM and LC_{50 MTT} ≥ 5.0 μM). The ability of selected stilbenes (RES, TPS and PIC) to exhibit growth inhibitory effects was also examined. Although RES and TPS were observed to inhibit cell proliferation in macrophages (IC₅₀ ≤ 25 μM), these cells were resistant to growth inhibition by PIC (IC₅₀ ≥ 50 μM). The data obtained in the present analysis demonstrate that substituted stilbene compounds such as RES have the capacity to exhibit cytotoxic and anti-proliferative activities in macrophages.     

Antihypoxic properties of endorphins, enkephalins and their analogs

The models of hypoxic hypoxia have been created in the experiments on mice by two ways: placing them into hermetic chamber or "lifting" them to 10.500-10.700 metres in the altitude chamber. The influence of enkephalins and their 12 analogs on the resistance of mice to hypoxia was tested. Enkephalin analogs with antihypoxic activities were detected using both models. It was shown that the mechanism of antihypoxic influence of opioids involves stimulation of their mu- and sigma-receptors and that other neurochemical systems of the body also take part in the realization of antihypoxic effects of the peptides. It is suggested that leu-enkephalin and des-tyr1-gamma-endorphin play, most likely, a role of endogenous antihypoxic agents.     

Synthesis and antitumor activity of novel amsacrine analogs: The critical role of the acridine moiety in determining their biological activity

A new series of N-[4-(2′-oxo-2H-pyrano[2,3-b]quinolin-5′-ylamino)-phenyl]-methanesulfonamides was prepared and analyzed as novel amsacrine-like derivatives. Our preliminary biological evaluation has shown that the replacement of the acridine moiety with the analogous 2-oxo-2H-pyrano[2,3-b]quinoline system drastically reduced both their anticancer activity and their propency to intercalate into double stranded DNA.     

Synthesis of the chromophores of fluorescent proteins and their analogs

Members of the green fluorescent protein (GFP) family are widely used in experimental biology as genetically encoded fluorescent tags. Chromophores of GFP-like proteins share a common structural core: 3,5-dihydro-4H-imidazol-4-one. This review covers synthetic approaches to 3,5-dihydro-4H-imida-zol-4-ones, substituted at different positions. General, as well as specific methods, represented by single examples are considered. The most popular synthetic route to substituted 3,5-dihydro-4H-imidazol-4-ones includes synthesis of azlactones, followed by transformation into N-acyldehydroamino acids and, finally, cyclization into target heterocycles. Accordingly, the review is divided into three parts: the first part covers syntheses of azlactones, the second part covers main approaches to N-acyldehydroamino acids, and in the third part we summarize cyclizations of N-acyldehydroamino acids, as well as all other approaches to 3,5-dihydro-4H-imidazol-4-ones.     

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 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 properties of 3'-desamino- dimethylformamidine doxorubicin

Interaction of doxorubicin hydrochloride with dimethylformamide diethylacetal yielded hydrochloride of 3'-desamino-3'-dimethylformamidine doxorubicin (DFD). It was shown that with single intravenous administration to tumor-free mice DFD was 2.5 times less toxic than the initial doxorubicin. Antitumor activity of DFD was studied with respect to 6 transplantable murine tumors: lymphosarcoma LIO-1, sarcoma 180, lymphadenosis NK-Ly, Ehrlich carcinoma, hemocytoblastosis La and leukemia P-388. Selectivity of the DFD activity against all the above tumors was shown to be high and practically equal to that of doxorubicin. DFD had the highest inhibitory effect on development of Ehrlich carcinoma and lymphosarcoma LIO-1.