Biological potential and structure-activity relationships of most recently developed vascular disrupting agents: an overview of new derivatives of natural combretastatin a-4.

Tumor blood vessels are an important emerging target for anti-cancer therapy. The antimitotic agent combretastatin A-4 (CA-4), a cis-stilbene natural product isolated from the South African tree Combretum caffrum Kuntze, is the lead compound of a new class of anti-cancer drugs that target tumor vasculature. CA-4 inhibits tubulin polymerization by interacting at the colchicine binding site on tubulin. This alters the morphology of endothelial cells and causes vascular shutdown and regression of tumor vasculature. Some tubulin-binding vascular-disrupting agents (VDAs) are currently in clinical trials for cancer therapy. As a consequence of the potential favorable applications of these compounds, several analogs projected to induce rapid and selective vascular shutdown in tumors have been synthesized during the last few years. Many of these molecules have already been tested for their effects on tubulin polymerization as well as for their antiproliferative activity and other biological properties, and possible mechanisms of action have been investigated. The aim of the present review is to offer an overview of most recently developed combretastatin derivatives, focusing on biological effects exerted by these compounds. The published data about new analogs are presented and compared, and a detailed investigation of structure-activity relationships is described.

Acronycine derivatives: a promising series of anticancer agents.

The pyranoacridone acronycine (1) exhibits antitumor properties against a large panel of solid tumor models, but its moderate potency and low water solubility severely hampered the subsequent clinical trials. Development of synthetic analogues followed the isolation from several Sarcomelicope species of acronycine epoxide (17), which led to a hypothesis of bioactivation of acronycine by transformation of the 1,2-double bond into the corresponding oxirane. 1,2-Diacyloxy-1,2-dihydroacronycine derivatives exhibited antitumor properties, with a broadened spectrum of activity and an increased potency. The demonstration that acronycine interacted with DNA led to the development of benzo[a], [b], and [c]acronycine analogs. 1,2-Dihydroxy-1,2-dihydrobenzo[b]acronycine esters and diesters were active in human orthotopic models of cancers xenografted in nude mice. The activity of these compounds, exemplified by cis-1,2-diacetoxy-1,2-dihydrobenzo[b]acronycine (49), developed in phase I clinical trials under the code S23906-1, was correlated with their ability to give covalent adducts with DNA, involving reaction between the N-2 amino group of guanines in the minor groove and the ester group at the benzylic position of the drug. The influence of the kinetics of DNA alkylation on the cytotoxic and antitumor properties showed a strong correlation between antiproliferative activity and DNA alkylation kinetics, with the most cytotoxic compounds, appearing as the slowest DNA alkylators. Hybrid compounds associating the acridone or benzo[b]acridone chromophore of acronycine derivatives and the epoxyfuran alkylating unit present in psorospermin also displayed potent antiproliferative activities, alkylating DNA guanine units at position N-7 in the major groove, as natural xanthones belonging to the psorospermin series.

Triterpenoids from Drypetes chevalieri Beille (euphorbiaceae).

The CH2Cl2/CH3OH (1/1) extract of the dried stem of Drypetes chevalieri Beille afforded two new triterpenoïds named drypechevalin A (11-oxo-beta-amyrin-3beta-ylcaffeate) and drypechevalin B (3,7-dioxo-D:A-friedooleanan-24-al) along with five known compounds: lupeol, lupeone, erythrodiol, putranjivadione, friedelin. Their structures were established on the basis of spectroscopic analysis and chemical evidence.

Components and antibacterial activity of the roots of Salvia jaminiana.

The acetone extract of the roots of Salvia jaminiana, containing the sterols campestanol, stigmasterol and sitosterol, and five known diterpenoids, ferruginol, cryptanol, 6,7-dehydroroyleanon, 6-hydroxysalvinolone and microstegiol, remarkably inhibited the growth of Bacillus subtilis, Staphylococcus aureus ATCC 25923 and Streptococcus alpha-hemolitic.

[New antitumor agents in the acronycine series]. / Conception de nouveaux agents antitumoraux en série acronycine.

The acridone alkaloid acronycine, isolated from several Sarcomelicope species (Rutaceae) was shown to exhibit a promising activity against a broad spectrum of solid tumors. Nevertheless, clinical trials only gave poor results, probably due to the moderate potency of this drug. The isolation of the unstable acronycine epoxide from several New-Caledonian Sarcomelicope led us to a hypothesis of bioactivation of acronycine by transformation of the 1,2-double bond into the corresponding oxirane in vivo. Consequently, we synthesized a series of cis-1,2-dihydroxy-1,2-dihydroacronycine diesters which exhibited interesting antitumor properties with a broadened spectrum of activity and an increased potency when compared with acronycine. The demonstration that acronycine should interact with DNA, by some noncovalent process prompted us to develop benzo[b] acronycine analogs possessing an additional aromatic ring linearly fused on the natural alkaloid basic skeleton. When tested against a panel of cancer cell lines in vitro, cis-1,2-dihydroxy-1,2-dihydrobenzo[b] acronycine diesters exhibited cytotoxic activities within the same range of potency as the most active drugs currently used in cancer chemotherapy. In vivo, cis-1,2-diacetoxy-1,2-dihydrobenzo[b] acronycine (S 23906-1), selected for further preclinical development, demonstrated a marked antitumor activity in human orthotopic models of lung, ovarian and colon cancers xenografted in nude mice.

Chalconoid and stilbenoid glycosides from Guibourtia tessmanii.

Phytochemical studies on the stem bark of Guibourtia tessmanii yielded a dihydrochalcone glucoside, 2',4-dihydroxy-4'-methoxy-6'-O-beta-glucopyranoside dihydrochalcone and a new stilbene glycoside, 3,5-dimethoxy-4'-O-(beta-rhamnopyranosyl-(1-->6)-beta- glucopyranoside) stilbene besides the known pterostilbene. Their structures were established on the basis of one and two dimensional NMR spectroscopic techniques, FABMS and chemical evidence.

Design of selectively activated anticancer prodrugs: elimination and cyclization strategies.

Cancer chemotherapy is associated with severe side effects which may be reduced by selective liberation, at the tumour site, of a cytotoxic agent from a non-toxic prodrug. Several strategies are used to achieve the required selective activation: with enzymes which are present in higher concentration in, or close, to the tumour (beta-glucuronidase, plasmin), with enzymes covalently linked to a macromolecular carrier able to recognize antigen positive cancer cells (ADEPT: Antibody Directed Enzyme Prodrug Therapy) or with reductive processes which are favoured in an hypoxic environment. Most of the prodrugs include a linker (or spacer) between the trigger and the drug (or effector). The design of such linkers is crucial in order to achieve a fast drug liberation under physiological conditions. The linker groups may be classified in two categories based on elimination or cyclization processes. The advantages and the limitations of each strategy are discussed.

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.

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.

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.

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.

A new diprenyl coumarin and alkaloids from the bark of Zanthoxylum dimorphophyllum (Rutaceae).

The alkaloids chelerythrine, norchelerythrine, oxyavicine, canthine-6-one, 4,5-dihydrocanthin-6-one, and gamma-fagarine were isolated from Zanthoxylum dimorphophyllum bark, together with two coumarins, scoparone and dimoxylin. This latter is a novel compound whose structure was elucidated on the basis of its spectral data.

Synthesis and cytotoxic activity of benzophenanthrolinone analogues of acronycine.

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.

Selective amination of secoiridoid glycosides to give monomeric pyridine, dimeric pyridine, and naphthyridine alkaloids.

Treatment of the secoiridoids oleuropein (4), ligstroside (5) and methyloleoside (6) by beta-D-glucosidase in the presence of ammonium chloride led exclusively to monomeric pyridine alkaloids 7, 1, and 8. Dimeric 3,4,5-trisubstituted pyridines were obtained from methyloleoside (6) when ammonium chloride was generated in the reaction mixture by successive additions of ammonia and hydrochloric acid. The use of ammonium acetate permitted conversion of secoiridoids 4 and 5 into the naphthyridine alkaloid jasminine (3).

Marked antitumor activity of a new potent acronycine derivative in orthotopic models of human solid tumors.

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.

Synthesis and cytotoxic activity of benzopyranoxanthone analogues of benz.

Condensation of 3-hydroxy-2-naphthalenecarboxylic acid with phloroglucinol afforded 1,3-dihydroxy-12H-benzo[b]xanthen-12-one. Construction of an additional dimethylpyran ring onto this skeleton, by alkylation with 3-chloro-3-methyl-1-butyne followed by Claisen rearrangement, gave access to a series of benzo[b]pyrano[2,3-i]xanthen-6-ones and benzo[b]pyrano[3,2-h]xanthen-7-ones related to psorospermine and benzo[b]acronycine. In contrast with what is observed in the pyridoacridone and benzopyridoacridone series, the linear benzo[b]-pyrano[2,3-i]xanthen-6-one derivatives were more potent than their angular benzo[b]pyrano[3,2-h]xanthen-7-one isomers. cis-3,4-Diacetoxy-5-methoxy-2,2-dimethyl-3,4-dihydro-2H,6H-benzo[b]pyrano[2,3-i]xanthen-6-one, the most active among the new compounds, was more potent than acronycine in inhibiting the proliferation of L1210 murine leukemia cells.

Furomegistines I and II, two furanopyridine alkaloids from the bark of Sarcomelicope megistophylla.

Two alkaloids, furomegistine I (1) and furomegistine II (2), were isolated from the bark of Sarcomelicope megistophylla. Their structures have been elucidated on the basis of MS and NMR data. Both belong to the category of furanopyridine alkaloids and should be considered as oxidation products of a furo[2,3-b]quinoline precursor. The two alkaloids exhibited moderate cytotoxic activity.

Homarine, a common metabolite in edible Mediterranean molluscs: occurrence, spectral data and revision of a related structure.

Homarine was isolated from nine edible species of marine molluscs belonging to classes Gastropoda, Bivalvia, and Cephalopoda. A thorough chromatographic, NMR and MS study provided evidence that homarine is a common and abundant metabolite of all these species. This study casts doubt on a previous assertion that 1,1'-dimethyl-[2,2']-bipyridinium is a metabolite of the Bivalve Callista chione.

Sesquiterpene lactone and friedelane derivative from drypetes molunduana.

A new sesquiterpene lactone, drypemolundein A and a new friedelane derivative, drypemolundein B, along with seven known compounds have been isolated from the whole stems of Drypetes molunduana Pax and Hoffm. Their structures were established on the basis of one- and two-dimensional NMR, homo- and hetero-nuclear spectroscopic evidence.

Two major flavonoids from Ballota nigra.

Two lactoylate flavonoids, luteolin-7-lactate and luteolin-7-glucosyl-lactate were isolated from Ballota nigra. They should be used for the chemical standardization of this drug of medicinal interest.

The structure of sarcomejine: an application of long-range (1)H-(15)N correlation at natural abundance.

A new 4(1H)-quinolinone alkaloid, sarcomejine (1), has been isolated from the bark of Sarcomelicope megistophylla. Its structure has been elucidated on the basis of MS and NMR data and especially with a long-range (1)H-(15)N correlation NMR spectrum at natural abundance.

Synthesis and cytotoxic and antitumor activity of benzo[b]pyrano[3, 2-h]acridin-7-one analogues of acronycine.

Benzo¿bacronycine (6-methoxy-3,3,14-trimethyl-3, 14-dihydro-7H-benzo¿bpyrano¿3,2-hacridin-7-one, 4), an acronycine analogue with an additional aromatic ring linearly fused on the natural alkaloid basic skeleton, was synthesized in three steps, starting from 3-amino-2-naphthalenecarboxylic acid (5). Eight 1, 2-dihydroxy-1,2-dihydrobenzo¿bacronycine esters and diesters (17-24) were obtained by catalytic osmic oxidation, followed by acylation. All these compounds were significantly more cytotoxic than acronycine, when tested against L1210 leukemia cells in vitro. The potency of the cyclic carbonate 24 was in the range of the most active drugs currently used in cancer chemotherapy. Two selected diesters (17 and 24) were evaluated in vivo against P388 leukemia and colon 38 adenocarcinoma implanted in mice. Both compounds were markedly active at doses 16-fold lower than the dose of acronycine itself. Against colon 38 adenocarcinoma, compounds 17 and 24 were highly efficient, inhibiting tumor growth by more than 80%. Diacetate 17 was the most active, inhibiting tumor growth by 96% at 6.25 mg/kg, with two of seven mice being tumor-free on day 43.