Marked antitumor activity of a new potent acronycine derivative in orthotopic models of human solid tumors. (1/17)

S 23906-1 is a novel acronycine derivative selected on the basis of its potency in vitro. We investigated the antitumor activity of S 23906-1 against several murine transplantable tumors (C38 colon carcinoma, P388 leukemia, B16 melanoma, and Lewis lung carcinoma) and in orthotopic models of human lung (NCI-H460 and A549), ovarian (IGROV1 and NIH:OVCAR-3), and colorectal cancers (HCT116 and HT-29). Against established C38 colon carcinoma, S 23906-1 administered twice i.v. from 1.56-6.25 mg/kg markedly inhibited tumor growth. Treatment at the optimal dose (6.25 mg/kg) induced tumor regression in all of the mice. Acronycine was 16-fold less potent and only moderately active at the maximum tolerated dose, 100 mg/kg. Against other murine tumors of the former National Cancer Institute panel, S 23906-1 was either only moderately active or totally inactive. When evaluated in human orthotopic models, S 23906-1 given p.o. or i.v. demonstrated a marked antitumor activity against human carcinomas. In the two human lung cancer models, S 23906-1 increased the survival of the animals in a dose-dependent manner and induced treated versus control values of 162% (NCI-H460) and 193% (A549). Vinorelbine was less active, with treated versus control values of 119% and 174%, respectively. A significant survival benefit was also observed against the two i.p. ovarian tumors in which S 23906-1 was as active as paclitaxel, inducing 80% long-term survivors in the NIH:OVCAR-3 model. Lastly, S 23906-1 inhibited the growth of primary HT-29 and HCT116 colon tumors grafted onto the cecum as efficiently as irinotecan and eradicated the formation of lymph node, hepatic, and pulmonary metastases in the aggressive HCT116 model. The novel spectrum of activity of S 23906-1 compared with existing anticancer agents warrants further preclinical investigation.  (+info)

Synthesis and cytotoxic activity of benzophenanthrolinone analogues of acronycine. (2/17)

Condensation of either 2-bromobenzoic acid (4) or 2-chloro-3-nitrobenzoic acid (5) with suitable aminoquinolines 6-8 afforded phenylquinolylamines 9-13. Acid mediated cyclization gave the corresponding 12H-benzo[b][1,7]phenanthrolin-7-ones 14 and 15, and 12H-benzo[b][1,10]phenanthrolin-7-ones 16-18. Compounds 14, 16, and 17 were subsequently N-methylated to 6-demethoxyacronycine and acronycine analogues 19-21, whereas reduction of the aromatic nitro group of 18 gave the amino derivative 22. Unsubstituted 12H-benzo[b][1,10]phenanthrolin-7-ones 16, 17, 20, and 21 were devoid of significant cytotoxic activity, whereas 18 and 22, bearing a nitrogen substituent at position 11, were significantly active. Unsubstituted 12H-benzo[b][1,7]phenanthrolin-7-ones 14 and 19, which include a pyridine nitrogen in the same 4-position as the pyran oxygen of acronycine exhibited cytotoxic activities within the same range of magnitude as acronycine itself.  (+info)

1-Oxo-2-hydroxy-1,2-dihydroacronycine: a useful synthon in the acronycine series for the introduction of amino substituents at 6-position and for the conversion into isopropylfuroacridones. (3/17)

Thermic aromatic nucleophilic displacement of the methoxy group at C-6 of (+/-)-1-oxo-2-hydroxy-1,2-dihydroacronycine (2) by an amine is a reaction that gives a facile entry to acronycine derivatives bearing an amino substituent at this position. The introduction of the amino substituents was confirmed with a long-range 1H-15N correlation NMR spectrum at natural abundance. Under basic conditions, compound 2 can also be rearranged to the corresponding isopropylfuroacridone 12, in 80% yield.  (+info)

Induction of cyclin E and inhibition of DNA synthesis by the novel acronycine derivative S23906-1 precede the irreversible arrest of tumor cells in S phase leading to apoptosis. (4/17)

S23906-1 is a diester derivative of 1,2-dihydrobenzo[b]acronycine with an unknown mechanism of action. This cytotoxic compound was 20-fold more potent than acronycine in inhibiting the proliferation of six tumor cell lines. Using a clonogenic assay of cell survival, the HT29 human colon carcinoma cell line was 100-fold more sensitive to S23906-1 than acronycine. Cell cycle analysis, by flow cytometry, showed that S23906-1 induced a partially reversible arrest of HT29 cells in G2+M at 1 microM and below and an irreversible arrest in S phase at 2.5 microM and above. These cell cycle effects were followed by cell death through apoptosis, quantified by annexin-V labeling. Inhibition of DNA synthesis was observed by complete prevention of bromodeoxyuridine (BrdU) incorporation after only 4 h of incubation with 5 microM S23906-1. Interestingly, under the same experimental conditions, a significant increase of cyclin E protein level was observed without any modification of cyclins D1, D2, D3, or A. This overexpressed cyclin E protein was not complexed with Cdk2, as shown by western blotting for Cdk2 in immunoprecipitates of cyclin E. Similar inhibition of BrdU incorporation and elevation of cyclin E protein were observed after treatment with cytosine arabinoside, which reversibly inhibited progression into S phase, but not after DNA damage induced by cisplatin. S23906-1 thus has a novel mechanism of action. A cell line resistant to S23906-1 showed that overexpression of cyclin E was implicated in the novel cytotoxic activity of this compound.  (+info)

Covalent binding to glutathione of the DNA-alkylating antitumor agent, S23906-1. (5/17)

The benzoacronycine derivative, S23906-1, was characterized recently as a novel potent antitumor agent through alkylation of the N2 position of guanines in DNA. We show here that its reactivity towards DNA can be modulated by glutathione (GSH). The formation of covalent adducts between GSH and S23906-1 was evidenced by EI-MS, and the use of different GSH derivatives, amino acids and dipeptides revealed that the cysteine thiol group is absolutely required for complex formation because glutathione disulfide (GSSG) and other S-blocked derivatives failed to react covalently with S23906-1. Gel shift assays and fluorescence measurements indicated that the binding of S23906-1 to DNA and to GSH are mutually exclusive. Binding of S23906-1 to an excess of GSH prevents DNA alkylation. Additional EI-MS measurements performed with the mixed diester, S28053-1, showed that the acetate leaving group at the C1 position is the main reactive site in the drug: a reaction scheme common to GSH and guanines is presented. At the cellular level, the presence of GSH slightly reduces the cytotoxic potential of S23906-1 towards KB-3-1 epidermoid carcinoma cells. The GSH-induced threefold reduction of the cytotoxicity of S23906-1 is attributed to the reduced formation of lethal drug-DNA covalent complexes in cells. Treatment of the cells with buthionine sulfoximine, an inhibitor of GSH biosynthesis, facilitates the formation of drug-DNA adducts and promotes the cytotoxic activity. This study identifies GSH as a reactant for the antitumor drug, S23906-1, and illustrates a pathway by which GSH may modulate the cellular sensitivity to this DNA alkylating agent. The results presented here, using GSH as a biological nucleophile, fully support our initial hypothesis that DNA alkylation is the major mechanism of action of the promising anticancer drug S23906-1.  (+info)

Synthesis and cytotoxic and antitumor activity of 1,2-dihydroxy-1,2-dihydrobenzo[b]acronycine diacid hemiesters and carbamates. (6/17)

A series of cis-1,2-dihydroxy-1,2-dihydrobenzo[b]acronycine diacid hemiesters and dicarbamates were prepared by acylation of cis-1,2-dihydroxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b]pyran o[3,2-h]acridin-7-one. The cytotoxicity of the dicarbamates depended on the steric hindrance of the esterifying groups at positions 1 and 2. Diacid hemiesters displayed significant in vitro cytotoxic activities and induced cell cycle perturbations similar to those obtained with cis-1,2-diacetoxy-1,2-dihydrobenzo[b]acronycine (S23906-1) currently under preclinical development. cis-1-Acetoxy-2-hemiglutaryloxy-1,2-dihydrobenzo[b]acronycine was the most promizing compound of the series, inducing complete inhibition of tumor growth when tested against C38 colon adenocarcinoma implanted in mice.  (+info)

Synthesis and cytotoxic activity of pyranocarbazole analogues of ellipticine and acronycine. (7/17)

Various 2,2,5,11-tetramethyl- and 2,2,5,6,11-pentamethyl-2,6-dihydropyrano[3,2-b]carbazole derivatives were synthesized by condensation of 3-methylbut-2-enal or 3-chloro-3-methylbut-1-yne with an appropriate hydroxycarbazole. These compounds associate the tricyclic system responsible for the intercalating properties of ellipticine related drugs, with the dimethylpyran pharmacophore of acronycine derivatives. The study of the biological properties of the new pyrano[3,2-b]carbazole derivatives was carried out in vitro on L1210 murine leukaemia cell line. The three (+/-)-cis-diol diesters 15, 16, and 18 were the most active compounds.  (+info)

Covalent binding of antitumor benzoacronycines to double-stranded DNA induces helix opening and the formation of single-stranded DNA: unique consequences of a novel DNA-bonding mechanism. (8/17)

The majority of DNA-binding small molecules known thus far stabilize duplex DNA against heat denaturation. A high, drug-induced increase in the melting temperature (Tm) of DNA is generally viewed as a good criterion to select DNA ligands and is a common feature of several anticancer drugs such as intercalators (e.g., anthracyclines) and alkylators (e.g., ecteinascidin 743). The reverse situation (destabilization of DNA to facilitate its denaturation) may be an attractive option for the identification of therapeutic agents acting on the DNA structure. We have identified the tumor-active benzoacronycine derivative S23906-1 [(+/-)-cis-1,2-diacetoxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[ b]pyrano[3,2]acridin-7-one] as a potent DNA alkylating agent endowed with a helicase-like activity. Using complementary molecular approaches, we show that covalent binding to DNA of the diacetate compound S23906-1 and its monoacetate analogue S28687-1 induces a marked destabilization of the double helix with the formation of alkylated ssDNA. The DNA-bonding properties and effects on DNA structure of a series of benzoacronycine derivatives, including the dicarbamate analogue S29385-1, were studied using complementary biochemical (electromobility shift assay, nuclease S1 mapping) and spectroscopic (fluorescence and Tm measurements) approaches. Alkylation of guanines in DNA by S28687-1 leads to a local denaturation of DNA, which becomes susceptible to cleavage by nuclease S1 and significantly decreases the Tm of DNA. The drug also directly alkylates single-strand DNA, but mass spectrometry experiments indicate that guanines in duplexes are largely preferred over single-stranded structures. This molecular study expands the repertoire of DNA-binding mechanisms and provides a new dimension for DNA recognition by small molecules.  (+info)

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