Artoindonesianin L, a new prenylated flavone with cytotoxic activity from Artocarpus rotunda.

A new prenylated flavone, named artoindonesianin L (1), was isolated from Artocarpus rotunda (Hout) Panzer (Moraceae). Its structure was elucidated as on the basis of spectroscopic evidence. Along with this new compound, four known phenolic compounds were also isolated from this plant and identified as artonins M (2) and E (3), cycloartobiloxanthone (4) and artonin O (5). All these compounds showed significant cytotoxicity against murine P388 leukemia cells.

Celogentins A-C, new antimitotic bicyclic peptides from the seeds of Celosia argentea.

Three new bicyclic peptides, celogentins A (1), B (2), and C (3), have been isolated together with a known-related peptide, moroidin (4), from the seeds of Celosia argentea, and their structures including absolute stereochemistry were determined by using extensive NMR methods and chemical means. Celogentins A (1), B (2), and C (3) inhibited the polymerization of tubulin, and celogentin C (3) was four times more potent than moroidin (4) in the inhibitory activity. Structure-activity relationship study using moroidin derivatives 5-7 and analogue 8 as well as celogentins A-C (1-3) and moroidin (4) indicates that the bicyclic ring system including unusual non-peptide connections among beta(s)-Leu, Trp, and His residues characteristic of celogentins and moroidin, with ring size and conformations suitable for interaction with tubulin would be important for their biological activity.

The cytotoxicity and chemical constituents of the hexane fraction of Typhonium flagelliforme (Araceace).

The plant, Typhonium flagelliforme (Araceae), commonly known as the "rodent tuber" in Malaysia, is often used as an essential ingredient of herbal remedies for alternative cancer therapies. The hexane extract of this plant was evaluated for cytotoxic activity against in vitro culture on P388 murine leukaemia cells and showed weak IC(50) of 15 microg/ml. The partial chemical constituents were identified as methyl esters of hexadecanoic acid, octadecanoic acid, 9-octadecenoic acid and 9,12-octadecadienoic acid. In addition, several common aliphatics were identified as dodecane, tridecane, tetradecane, pentadecane, hexadecane, heptadecane, octadecane, nonadecane and eicosane. The unique methyl ester of 13-phenyltridecanoic acid was isolated and positively identified using spectroscopic methods. None of the identified compounds showed or are known to have cytotoxic behaviour.

Cytotoxic activity of Typhonium flagelliforme (Araceae).

The plant Typhonium flagelliforme (Araceae), commonly known as the 'rodent tuber', is often included as an essential ingredient in various herbal remedies recommended for cancer therapies in Malaysia. Various extracts prepared from either the roots, tubers, stems or leaves were tested for cytotoxic activity on murine P388 leukaemia cells using the MTT assay method. Both the chloroform (IC50 = 6.0 microg/mL) and hexane (IC50 = 15.0 microg/mL) extract from the 'roots and tubers' exhibited weak cytotoxic activity. The hexane extract (IC50 = 65.0 microg/mL) from the 'stems and leaves' exhibited weaker cytotoxic activity than the chloroform extract (IC50 = 8.0 microg/mL). Although the juice extract from the 'roots and tubers' is frequently consumed for cancer treatment, it exhibited poor cytotoxic activity. Further analysis using an amino acid analyser revealed that the juice extract contained a high concentration of arginine (0.874%). A high tryptophan content (0.800%) was confirmed by NMR and HPLC analysis.

Protective effect of SM-20550, a selective Na+ - H+ exchange inhibitor, on ischemia-reperfusion-injured hearts.

The protective effects of Na+ - H+ exchange inhibitors SM-20550 (SM) and 5-(N-ethyl-N-isopropyl)-amiloride (EIPA) against ischemia-reperfusion injury were investigated in guinea pig Langendorff hearts. The changes in intracellular pH (pHi), high-energy phosphates, and biologic intracellular active ions ([Na+]i and [Ca2+]i) were regarded using the 31P-NMR and specific fluorescent signals from the heart tissues together with simultaneous recordings of the left ventricular developed pressure (LVDP). The recovery rate of LVDP from ischemia (40 min) by reperfusion was 36.8% in the control experiments, whereas in the presence of SM 10(-7) M, a gradual increase to 75.9% (55.5% with 10(-8) M), in contrast to EIPA (10(-7) M), 47.5% was observed. SM 10(-7) M restored the ATP level by 70% in 40-min reperfusion, which was already higher than the control in the latter half (20-40 min) of the ischemic period. The recovery rate of phosphocreatine by pretreatment of the heart with SM 10(-7) M was 75% in 40 min reperfusion. The pHi estimated from Pi/phosphocreatine chemical shift became highly acidic in ischemic heart so that SM 10(-7) M caused slight but significant pHi reduction from control pHi of 5.89 to 5.75. The level returned to pHi at around 7.38 during 30-40 min reperfusion, and the recovery was significantly greater than the control pHi of 7.24. The fura-2 Ca2+ or SBFI-Na+ signals during Langendorff ischemia heart increased, and rapidly returned to the control level after the reperfusion. SM suppressed the [Na+]i or [Ca2+]i elevation induced in the late stage during ischemia, resulting in LVDP restoration after reperfusion; Diastolic Ca2+ in the end period of ischemia, SM 10(-7) M 194% versus drug-free 220.7%. Na+: SM 10(-7) M 121.6% versus drug-free 128.0%. The present results suggest that the selective Na+ - H+ exchange inhibitor SM is promising as a potent and specific protective agent against ischemia-reperfusion injuries with Ca2+ overload induced via Na+ - H+, Na+ - Ca2+ exchange.

Cedronolactone E, a novel C(19) quassinoid from Simaba cedron.

A novel pentacyclic C(19) quassinoid, cedronolactone E (1), was isolated from the wood of Simaba cedron. Its structure was elucidated by interpretation of spectroscopic data.

4-Aza-2,3-dehydro-4-deoxypodophyllotoxins: simple aza-podophyllotoxin analogues possessing potent cytotoxicity.

4-Aza-2,3-dehydro-4-deoxypodophyllotoxin analogues 3a-n were synthesized through quinolines 2a-n. Comparison of their cytotoxicity against P-388 leukemia cells revealed that the steric effects of the ring B substituents on the activity are greater than the electronic effects, while the presence of a methoxy group on the ring E is not essential to exhibit potent cytotoxicity. Analogues 3a and 3b proved to be more than twice as cytotoxic as natural podophyllotoxin (1).

Steroidal saponins from the leaves of Cestrum sendtenerianum.

Five steroidal saponins were isolated from the EtOH extract of Cestrium sendtenerianum (Solanaceae), as confirmed by detailed analysis of their 1H, 13C, and two-dimensional NMR spectral data, and by the results of hydrolytic cleavage. The saponins were revealed to contain three hydroxyl groups at the C-1beta, C-2alpha, and C-3beta positions in the spirostanol skeleton, and to bear a di- or triglycoside at C-3 as the common structural features. One of the compounds, a spirostanol triglycoside, showed weak cytotoxic activity on HL-60 human promyelocytic leukemia cells, with an IC50 value of 7.7 microg/ml.

[Antitumor compounds isolated from higher plants].

A lot of anticancer agents have been isolated from natural sources, especially from microorganisms and plants. However, there is no special type of compounds for cancer therapy. Various types of substances are effective for various types of cancers and tumors: for instance, alkaloids, lignans, terpenes and steroids, etc. In this report, the authors will describe especially about higher plants.

Structure-cytotoxic activity relationship for the toad poison bufadienolides.

The toad poison bufadienolides including natural and derivatized compounds were tested for their cytotoxic effects on primary liver carcinoma cells PLC/PRF/5 and their structure-cytotoxic activity relationships were studied. For this study, a ligand-binding model was developed by using a pharmacophore mapping program, Distance Comparisons (DISCO). The structural features that are common to the 3D structures of active bufadienolides were identified to provide approach to a 3D QSAR method by using Comparative Molecular Field Analysis (CoMFA) study and to correlate the steric and electrostatic fields of the molecules to their activities. A valuable model which enables prediction of their activities was obtained from the CoMFA analysis, which may be employed for the drug designs of new bufadienolide analogues.

Cytotoxic quassinoids from Simaba cedron.

Four new quassinoids, cedronolactones A-D (1-4), together with nine known compounds, simalikalactone D (5), chaparrinone (6), chaparrin (7), glaucarubolone (8), glaucarubol (9), samaderine Z (10), guanepolide (11), ailanquassin A (12), and polyandrol (13), were isolated from the wood of Simaba cedron. The chemical structures of 1-4 were elucidated on the basis of their chemical and spectral properties. Cedronolactone A (1) was shown to exhibit a significant in vitro cytotoxicity (IC50 0.0074 microg/mL) against P-388 cells.

Cytotoxic flavonoids from Vitex agnus-castus.

Four new flavonoids, luteolin 6-C-(4"-methyl-6"-O-trans-caffeoylglucoside), luteolin 6-C-(6"-O-trans-caffeoylglucoside), luteolin 6-C-(2"-O-trans-caffeoylglucoside), and luteolin 7-O-(6"-p-benzoylglucoside), together with four known ones 5, 4'-dihydroxy-3,6,7,3'-tetramethoxyflavone, luteolin, artemetin and isorhamnetin, were isolated from the root bark of Vitex agnus-castus. The structures were elucidated by spectroscopic means.

Cyclic octapeptides from Stellaria dichotoma var. lanceolata.

Two new cyclic octapeptides, dichotomin H, cyclo(-Ala-Pro-Thr-Phe-Tyr-P ro-Leu-Ile-), and dichotomin I, cyclo(-Val-Pro-Thr-Phe-Tyr-Pro-Leu-Ile-) have been isolated from the roots of Stellaria dichotoma L. var lanceolata Bge., and their structures were elucidated by extensive two-dimensional NMR methods and chemical degradation.

Taxuspinananes A and B, new taxoids from Taxus cuspidata var. nana.

New taxoids, taxuspinanane A (1), showing potent cytotoxic activity, and taxuspinanane B (2), have been isolated from the stems of Taxus cuspidata Sieb. et. Zucc. var. nana Rehder. Their structures were elucidated by extensive 2D NMR and MS spectroscopic analysis.

Studies on cardiac ingredients of plants. XIII: Chemical modification of gitoxin to cardiotonic compounds without vascular effect.

Nitrated gitoxins (4) and bufotoxin homologues with various lengths of alkyl chain at C-3 of the steroid nucleus (10) were prepared from gitoxin (1). The pharmacological activities of the resulting compounds (4 and 10) were evaluated by measurement of inhibitory effect on NA+, K(+)-adenosine triphosphatase (ATPase) prepared from dog kidney, positive inotropic effect (PIE) on isolated guinea-pig papillary muscle preparations, and the effect on smooth muscle using the mesenteric artery from spontaneously hypertensive rats. Most of the compounds showed a smaller contractile effect on the arterial muscle. Among these compounds, gitoxin 3"-nitrate (4g) exhibited the most desirable biological activities, such as PIE comparable to that of 1, 1.25 times wider concentration-dependent range than 1, and lack of contractile activity on vascular muscle.

Cyclic peptides from higher plants. 34. Segetalins G and H, structures and estrogen-like activity of cyclic pentapeptides from Vaccaria segetalis.

Segetalins G and H (1-2) possessing estrogen-like activity are cyclic pentapeptides from the seeds of Vaccaria segetalis. Their structures, cyclo(-Gly-Ala-Lys-Tyr-Val) (1) and cyclo(-Gly-Phe-Ser-Tyr-Arg-) (2), were determined by interpretation of spectral data.

Thionation of segetalins A and B, cyclic peptides with estrogen-like activity from seeds of Vaccaria segetalis.

Thionation of estrogen-like active cyclic peptides, segetalins A (1) and B (2), with Lawesson's reagent provided each two thiosegetalins; thiosegetalin A1 [Gly-1-psi(CS-NH)-Val-2; Trp-5-psi (CS-NH)-Ala-6]segetalin A, thiosegetalin A2 [Gly-1-psi(CS-NH)-Val-2; Ala-6-psi(CS-NH)-Gly-1]segetalin A, thiosegetalin B1 [Gly-1-psi (CS-NH)-Val-2; Ala-3-psi(CS-NH)-Trp-4]segetalin B, and thiosegetalin B2 [Gly-1-psi(CS-NH)-Val-2; Trp-4-psi(CS-NH)-Ala-1]segetalin B. Thiosegetalin A2 only showed estrogen-like activity against ovariectomized rats. On the basis of their conformations analysed by NMR experiments, the backbone conformation was considered to play an important role in estrogen-like activity for segetalins.

Cytotoxic triterpenes from Cleome africana.

Eighteen dammarane-type triterpenes were obtained from the whole plant of Cleome africana by means of cytotoxic bioassay-directed fractionation. Twelve of them were novel compounds whose structures were elucidated by various spectroscopic methods.

Ester-type cephalotaxus alkaloids from Cephalotaxus harringtonia var. drupacea.

Three alkaloids, neoharringtonine, homoneoharringtonine and 3'S-hydroxyneoharringtonine, were isolated from the leaves and stems of Cephalotaxus harringtonia var. drupacea. Their structures were established by spectroscopic methods, including two-dimensional NMR and CD spectra, and their antileukaemic activity was evaluated using P-388 leukaemia cells.

Conformational preference for segetalins G and H, cyclic peptides with estrogen-like activity from seeds of Vaccaria segetalis.

Three-dimensional structures in DMSO-d0 of segetalins G [cyclo(-Gly-Val-Lys-Tyr-Ala-)] and H [cyclo(-Gly-Tyr-Arg-Phe-Ser-)], cyclic pentapeptides from seeds of Vaccaria segetalis, showing estrogen-like activity, were determined by the distance geometry calculation and restrained energy minimization from NMR data. The backbone structure of segetalin G contains one beta-turn: a beta II-like turn at Tyr4-Ala5, and that of segetalin H one beta-turn: a beta II' turn at Gly1-Tyr2 and one gamma-turn at Arg3-Phe4-Ser5 sequence. The results of distance comparison analysis proposed a pharmacophore model of estrogen-like cyclic peptides, segetalins.