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.

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.

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.

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.

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.

Synthesis and cytotoxic and antitumor activity of esters in the 1,2-dihydroxy-1,2-dihydroacronycine series.

Seven 1,2-dihydroxy-1,2-dihydroacronycine and 1,2-dihydroxy-1,2-dihydro-6-demethoxyacronycine esters and diesters were synthesized via osmic oxidation of acronycine or 6-demethoxyacronycine followed by acylation. The 6-demethoxyacronycine derivatives were found to be inactive, whereas in contrast, all of the acronycine derivatives were more potent than acronycine itself when tested against L1210 cells in vitro. Four selected acronycine derivatives (17,19, 21, and 22) were evaluated in vivo against murine P388 leukemia and colon 38 adenocarcinoma implanted in mice. All compounds were markedly active against P388 at doses 4-16-fold lower than acronycine itself. Against the colon 38 adenocarcinoma, the three compounds 17, 21, and 22 were highly efficient. 1,2-Diacetoxy-1,2-dihydroacronycine (17) was the most active, all the treated mice being tumor-free on day 23.

Prodrugs of anthracyclines for use in antibody-directed enzyme prodrug therapy.

A series of new prodrugs of daunorubicin and doxorubicin which are candidates for antibody-directed enzyme prodrug therapy (ADEPT) is reported. These compounds (25a,b,c and 32a,b,c) have been designed to generate cytotoxic drugs after activation with beta-glucuronidase. As expected, recovery of the active drug was observed after enzymatic cleavage by Escherichia coli beta-glucuronidase as well as by a fusion protein which has been obtained from human beta-glucuronidase and humanized CEA-specific binding region. The six prodrugs are highly stable and are more than 100-fold less cytotoxic than doxorubicin against murine L1210 cell lines. The ortho-substituted phenyl carbamates 25a,b,c are better substrates for beta-glucuronidase than the corresponding para-substituted analogues. After taking into account additional factors such as stability in plasma and kinetics of enzymatic cleavage, we selected the o-nitro prodrug 25c for clinical trials.

A phenylpropanoid glycoside from Ballota nigra.

A new phenylpropanoid glycoside, ballotetroside, has been isolated from the aerial parts of Ballota nigra. On the basis of chemical and spectral data, its structure has been established as (3,4-dihydroxyphenyl)-2-ethyl[alpha-L-arabinopyranosyl-(1-->2)-alp ha- L-rhamnopyranosyl-(1-->3)]-beta-D-apiofuranosyl-(1-->6)-4-O- caffeoyl-beta-D-glucopyranoside.

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.

Megistosarcimine and megistosarconine, two alkaloids from Sarcomelicope megistophylla.

Two new alkaloids, megistosarcimine and megistosarconine, were isolated from the aerial parts of Sarcomelicope megistophylla. Their structures have been elucidated on the basis of their spectral data and molecular modeling.

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.

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.

Efficient conversion of aucubin into 6-epi-aucubin

Selective deprotection of peracetylaucubin (3) by use of KCN led to 6-O-acetylaucubin (4), which was readily converted into 2',3',4',6', 10-penta-O-benzoylaucubin (7). Configuration inversion performed on 7, using a modified Mitsunobu reaction, followed by deprotection, afforded 6-epi-aucubin (2).

Polyoxygenated flavones from the leaves of comptonella microcarpa

The leaves of Comptonella microcarpa have yielded one alkaloid, dictamnine, and four known polyoxygenated flavonoids, meliternatin, 3,5,8-trimethoxy-6,7-3',4'-dimethylenedioxyflavone, 7-(3-methylbut-2-enyloxy)-3,5,8-trimethoxy-3', 4'-methylenedioxyflavone (3), 7-hydroxy-3,5,8-trimethoxy-3', 4'methylenedioxyflavone. In addition, two new flavonoids were found whose structures were established on the basis of their spectral data as 7-hydroxy-3,5,6,8-tetramethoxy-3',4'-methylenedioxyflavone (1) and 7-(3-methylbut-2-enyloxy)-3,5,6,8-tetramethoxy-3', 4'-methylenedioxyflavone (2).

Synthesis of a phenyl beta-avobioside derivative of the disaccharide component of avoparcins.

The synthesis of the phenyl beta-glycoside of avobiose, a disaccharide fragment present in the antibiotic avoparcin, is reported. It is based on glycosylation of phenyl 3,4,6-tri-O-benzyl-beta-D-glucopyranoside with 2,3,6-trideoxy-4-O-p-nitrobenzoyl-3-trifluoroacetamido-L-ribo-hex- 1-enitol, a fully protected glycal of L-ristosamine, in the presence of trimethylsilyl triflate.

Isolation and antibacterial activity of phenylpropanoid derivatives from Ballota nigra.

In addition to the previously isolated phenylpropanoid glycosides verbascoside 1, forsythoside B 2, arenarioside 3 and ballotetroside 4, another four compounds were isolated from generative aerial parts of Ballota nigra: three phenylpropanoid glycosides, alyssonoside 5, lavandulifolioside 6 and angoroside A 7 and a non-glycosidic derivative (+)-(E)-caffeoyl-L-malic acid 8. The antibacterial activity of the five major compounds (1-4 and 8) was tested against gram-positive and gram-negative bacteria. Three of them (1-3) exhibited a moderate antimicrobial activity against Proteus mirabilis and Staphylococcus aureus including one methicillin-resistant strain.

Megistolactone, a new alkaloid from Sarcomelicope megistophylla.

A new quinolone alkaloid, megistolactone (1) was isolated from the bark of Sarcomelicope megistophylla. Its structure has been elucidated on the basis of MS and NMR data. From a biogenetic point of view, this compound should be considered as an oxidation product of 1,2,3,4-tetra-O-subsituted acridone alkaloids, which are also present in the bark.

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.

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.

[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.