RESUMO
Triple-negative breast cancer (TNBC) is one of the most aggressive cancer with high mortality and recurrence rates. Hecogenin, a steroidal sapogenin, is reported as a potential anti-tumor agent against breast cancer. However, the moderate activity limits its further application in clinical. With the aim to identify novel analogues that are especially efficacious in therapy of TNBC, a series of novel hecogenin thiosemicarbazone and semicarbazone derivatives were designed, synthesized and biologically evaluated. Screening of cytotoxicity revealed that 4c could potently inhibit the proliferation of breast cancer cells (MCF-7 and MDA-MB-231 cells), lung cancer cells (A549) and colon cancer cells (HT-29) at low µM level. Importantly, further mechanism studies indicated the ability of 4c in inducing apoptosis of MDA-MB-231 cells by arresting the cell cycle. Moreover, 4c notably suppressed the migration and invasion of MDA-MB-231 cells compared to its parent hecogenin at the equal concentration.
Assuntos
Antineoplásicos/farmacologia , Sapogeninas/farmacologia , Tiossemicarbazonas/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana , Humanos , Sapogeninas/síntese química , Sapogeninas/toxicidade , Tiossemicarbazonas/síntese química , Tiossemicarbazonas/toxicidadeRESUMO
The BF3·Et2O-catalysed acetolysis of steroid sapogenins diosgenin, sarsasapogenin and tigogenin in dichloromethane as the solvent instead of acetic anhydride afforded (20S)- and (20R)-22,26-epoxycholestanes (compounds 1 and 2). 22S-23-Acetylsapogenins (compounds 4) were synthesized stereospecifically from 20R-22,26-epoxycholestanes (compounds 2) in good yield. The rearrangement of 22S-23-acetylsapogenins (compounds 4) afforded novel disubstituted dihydropyran furostanol frameworks. Exhaustive NMR characterization of the obtained compounds is provided. Additionally, the structures of the critical compounds (6a and 7a) were unequivocallyconfirmed by single crystal X-ray diffraction studies.
Assuntos
Sapogeninas/síntese química , Boranos , Catálise , Óxido de Etileno , Conformação Molecular , Sapogeninas/química , EstereoisomerismoRESUMO
The regioselective opening of the F ring of 22-oxo-23-spiroketals 7a-d using TiCl4 in acetic anhydride yielded the novel furostanols 11a-d along with cholestanic derivatives 8a-d with pyranone E ring. The structures of the new derivatives thus obtained were established using one- (DEPT) and two-dimensional 1H, 13C NMR experiments (COSY, HSQC, HMBC, NOESY). The 22α-hydroxyl orientation in compounds 11a-d was proposed by comparison of the 13C chemical shifts with those of other aglycone members of this family, and confirmed by combined NOESY and X-ray diffraction analysis of compound 11a.
Assuntos
Furanos/química , Glicosídeos/química , Sapogeninas/síntese química , Compostos de Espiro/química , Esteróis/química , Titânio/química , Catálise , Modelos Moleculares , Conformação Molecular , Sapogeninas/químicaRESUMO
Ginseng is a perennial herb that contains various medicinal substances. The major active constituents of ginseng are ginsenosides, which have multifarious biological activities. Some pharmacological activities are closely dependent on the stereoisomers derived from the configuration at C20. In this study, the in vitro anti-inflammatory activity of C20 epimeric ocotillol-type triterpenes (2, 3, 9: , and 10: ) and protopanaxadiol [20(S/R)-protopanaxadiol] were investigated. Epimers 2: and 3: were prepared starting from 20(S)-protopanaxadiol. Epimers 9: and 10: were synthesized from 20(R)-3-acetylprotopanaxadiol (7: ). The anti-inflammatory activity of 2, 3, 9, 10: , 20(S)-protopanaxadiol, and 20(R)-protopanaxadiol was evaluated in cultured mouse macrophage RAW 264.7 cells. The MTT assay was used to measure the cytotoxicity. RAW 264.7 cells were stimulated by lipopolysaccharide to release the inflammatory mediators nitric oxide, prostaglandin E2, TNF-α, and interleukin-6 and anti-inflammatory mediator interleukin-10. The effect of the compounds on the overproduction of nitric oxide, prostaglandin E2, TNF-α, interleukin-6, and interleukin-10 was determined using Griess and ELISA methods. The results demonstrated that the in vitro anti-inflammatory activities of C20 epimeric ocotillol-type triterpenes and protopanaxadiol were different. Both the 20S-epimers (2: and 3: ) and 20R-epimers (9: and 10: ) inhibited the release of inflammatory mediator nitric oxide, while mainly the 20S-epimers inhibited the release of inflammatory mediator prostaglandin E2, and the 20R-epimers inhibited the release of inflammatory cytokine TNF-α. Both the 20S-epimers [2, 3: , and 20(S)-protopanaxadiol] and 20R-epimers [9, 10: , and 20(R)-protopanaxadiol] inhibited the release of inflammatory cytokine interleukin-6, but mainly the 20S-epimers [2, 3: , and 20(S)-protopanaxadiol] increased the release of anti-inflammatory mediator interleukin-10.
Assuntos
Anti-Inflamatórios/farmacologia , Ginsenosídeos/farmacologia , Sapogeninas/farmacologia , Triterpenos/farmacologia , Animais , Anti-Inflamatórios/síntese química , Dinoprostona/antagonistas & inibidores , Ginsenosídeos/síntese química , Interleucina-10/metabolismo , Camundongos , Óxido Nítrico/antagonistas & inibidores , Panax/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Células RAW 264.7/efeitos dos fármacos , Sapogeninas/síntese química , Triterpenos/síntese química , Difração de Raios XRESUMO
Natural products have documented oncology success history as valuable scaffolds for selective target modulation. Herein, the sapogenin hecogenin (1) was screened for its anti-breast cancer inhibitory capacity using in vitro assays, including proliferation, cytotoxicity, migration, invasion assays, and Western blotting. The results identified 1 as a propitious hit with modest activities attributed to the concurrent down-regulation of mitogen activated protein kinase kinase/extracellular signal-regulated kinase (MEK) distinctive downstream effectors. Guided by in silico 3D-structural insights of MAPK kinase domain, an extension strategy was adopted at 1's C-3 and C-12 aimed at the design of novel hecogenin-based analogs with improved target binding affinity. Thirty-three analogs were prepared and tested, among which hecogenin 12-(3'-methylphenyl thiosemicarbazone) (30) displayed the most potent selective anticancer effects. Analog 30 demonstrated antiproliferative, antimigratory and anti-invasive activities at low µM level, compared to the negligible effect on the non-tumorigenic MCF-10A mammary epithelial cells. Durable regression of breast tumor xenografts in athymic nude mice was observed after treatments with 30, compared to its parent hecogenin at the same dose regimen, confirmed the hit-to-lead promotion of this analog. Hecogenin-12-thiosemicarbazones, represented by 30, is a novel MEK inhibitory lead class to control breast neoplasms.
Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Desenho de Fármacos , Inibidores de Proteínas Quinases/farmacologia , Sapogeninas/farmacologia , Tiossemicarbazonas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , MAP Quinase Quinase Quinases/antagonistas & inibidores , MAP Quinase Quinase Quinases/metabolismo , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Nus , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Sapogeninas/síntese química , Sapogeninas/química , Relação Estrutura-Atividade , Tiossemicarbazonas/síntese química , Tiossemicarbazonas/química , Células Tumorais CultivadasRESUMO
BF3·Et2O-catalyzed aldol condensation of steroid sapogenins with 2-formyl-estradiol diacetate afforded two novel classes of steroid dimers in which an estrogenic core is attached to the spirostanic side chain of an steroid sapogenin through an exocyclic double bond in position C-23, or through a spiro centre in C-22.
Assuntos
Aldeídos/química , Estradiol/síntese química , Sapogeninas/química , Esteroides/química , Aldeídos/síntese química , Benzaldeídos/síntese química , Benzaldeídos/química , Catálise , Estradiol/análogos & derivados , Estradiol/química , Espectroscopia de Ressonância Magnética , Sapogeninas/síntese química , Estereoisomerismo , Esteroides/síntese químicaRESUMO
Treatment of steroid sapogenins with H2O2 in CF3COOH for 15min followed by reflux in CH3OH/H2O afforded good yields of pregnan-3ß,16ß,20-triol 3-monoacetates. When the hydrolysis step was carried out with KOH in refluxing methanol excellent yields pregnantriols were obtained. The resulting compounds were characterized by their melting points and NMR spectral data. An X-ray diffraction analysis of compound 3a confirmed the proposed structure and provided detailed information about the bond lengths, bond angles and conformation.
Assuntos
Pregnanolona/química , Sapogeninas/química , Esteroides/química , Cristalografia por Raios X , Peróxido de Hidrogênio/química , Hidrólise , Espectroscopia de Ressonância Magnética , Conformação Molecular , Estrutura Molecular , Sapogeninas/síntese química , Estereoisomerismo , Esteroides/síntese química , Temperatura de TransiçãoRESUMO
Benzylidenespirostanols were prepared by two-step synthesis including BF3·Et2O-catalyzed aldol condensation of several acetylated steroid sapogenins with benzaldehyde followed by saponification. The obtained compounds showed moderate cytotoxicity against three cancer cell lines (T-lymphoblastic leukemia cell line CEM, breast carcinoma cell line MCF7 and cervical carcinoma cell line HeLa) and normal human fibroblasts (BJ). The most active of the five tested substances was 3c (lowest IC50 for MCF7 cells 19.9±0.1µM) without any selectivity towards human cancer and normal cells, respectively.
Assuntos
Antineoplásicos Fitogênicos/síntese química , Sapogeninas/síntese química , Espirostanos/síntese química , Esteroides/síntese química , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células MCF-7 , Sapogeninas/química , Sapogeninas/farmacologia , Espirostanos/química , Espirostanos/farmacologia , Esteroides/química , Esteroides/farmacologiaRESUMO
Corticosteroids are products of high industrial and commercial importance. There are dozens of different synthesis published for all of them. Some are coming from academia and some from industry. Here, industrial processes for the synthesis of prednisone, prednisolone, hydrocortisone, dexamethasone, betamethasone, and methylprednisolone are described. The starting material is diosgenin and the desired molecules are reached due to a good combination of chemistry and biotechnology that was developed along the second part of the twentieth century.
Assuntos
Corticosteroides/biossíntese , Hidrocortisona/biossíntese , Engenharia Metabólica/métodos , Sapogeninas/síntese química , Corticosteroides/síntese química , Corticosteroides/química , Hidrocortisona/química , Prednisolona/síntese química , Prednisolona/química , Prednisona/síntese química , Prednisona/química , Sapogeninas/químicaRESUMO
During the screening of natural anti-inflammatory agent, we identified some C21-steroidal pregnane sapogenins or the derivatives to inhibit TLR2, TLR3, and TLR4-initiatedinflammatory responses respectively. Treatment with active compounds 10, 2j and 3p failed to impact tumor necrosis factor-α (TNF-α) induced nucleus translocation of NF-κB p65 subunit. However, these compounds regulated distinct canonical or non-canonical NF-κB family members. Ectopic expression of TNF receptor associated factor 6 (TRAF6) abrogated the inhibitory activity of the compounds on production of pro-inflammatory cytokines downstream of TLR4. These results suggested that compounds 10, 2j, and 3p suppressed TLR-initiated innate immunity through TRAF6 with differential regulation of NF-κB family proteins.
Assuntos
Anti-Inflamatórios/farmacologia , Citocinas/antagonistas & inibidores , Sapogeninas/farmacologia , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Células Cultivadas , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Humanos , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Estrutura Molecular , Sapogeninas/síntese química , Sapogeninas/química , Relação Estrutura-AtividadeRESUMO
Protopanaxadiol (PPD) is an active compound in Panax ginseng. Recently, an optimized PPD synthesis pathway contained a ROS releasing step (a P450-type PPD synthase, PPDS) was introduced into Saccharomyces cerevisiae. Here reported a synergistic effect of PPDS-CPR (CPR, cytochrome P450 reductase) uncoupling and ethanol stress on ROS releasing, which reduced cells viability. To build a robust strain, a cell wall integrity associated gene SSD1 was high-expressed to improve ethanol tolerance, and ROS level decreased for 24.7%. Then, regulating the expression of an oxidative stress regulation gene YBP1 decreased 75.2% of ROS releasing, and improved cells viability from 71.3±1.3% to 88.3±1.4% at 84h. Increased cells viability enables yeast to produce more PPD through feeding additional ethanol. In 5L fermenter, PPD production of W3a-ssPy reached to 4.25±0.18g/L (19.48±0.28mg/L/OD600), which is the highest yield reported so far. This work makes the industrial production of PPD possible by microbial fermentation.
Assuntos
Fermentação , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Sapogeninas/síntese química , Sapogeninas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismoRESUMO
To explore the antitumour mechanism of 20(S)-protopanaxadiol (PPD) while maintaining its uncovered pharmacological active site 3-hydroxyl, 28-hydroxy protopanaxadiol (17), a small molecular probe template of PPD was first designed and synthesised based on the Baldwin's reaction. Thus, 28-hydroxyl of 17 was built successfully as a derivatized site of molecular probe's functional and report groups. The important intermediates and final product were confirmed by ESI-MS and nuclear magnetic resonance spectra with good yield. These studies provided a valuable basis for probe research of PPD.
Assuntos
Sondas Moleculares/síntese química , Sapogeninas/síntese química , Antineoplásicos/química , Domínio Catalítico , Análise EspectralRESUMO
A series of oxidized products have been systematically semisynthesized from 20(S)-ginsenoside Rg3, Rh2, 20(S)-protopanaxadiol (PPD) and their 20(R)-epimers and the majority of these products were evaluated for their cytotoxic activity against HeLa cells and HepG2 cells by MTT assay for the first time. Twenty-two products were obtained and elucidated based on comprehensive (1)H NMR, (13)C NMR, two-dimensional (2D) NMR, and mass spectral data and the results reported in previous literature. All the four ocotillol type saponins (20S,24R(δ86, δ85); 20S,24S(δ87, δ88); 20R,24R(δ86, δ86); 20R,24S(δ86, δ87) were obtained. In addition, eight compounds (3, 8, 9, 10, 15, 16, 19 and 22) with the cyclized side chain were firstly identified. Most of the tested compounds possessed cytotoxicity to a certain degree against the two types of cells which implied these oxidized products could play a certain role on anti-cancer functions of the raw materials in vivo. Meanwhile, the results proved that the configurations at C-20 or C-24 and the number of glycosyl at C-3 have important influence on the cytotoxicity. The products 1, 2, 11-17, 20 and 22 should possess great activities and deserved further investigation as potential cytotoxic agents.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Triterpenos/síntese química , Triterpenos/farmacologia , Antineoplásicos/química , Técnicas de Química Sintética , Ginsenosídeos/síntese química , Ginsenosídeos/química , Ginsenosídeos/farmacologia , Células HeLa , Células Hep G2 , Humanos , Oxirredução , Sapogeninas/síntese química , Sapogeninas/química , Sapogeninas/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Triterpenos/químicaRESUMO
A divergent synthesis of three core pentacyclic lactones of nine rearranged cholestane sapogenins, saundersiosides A-H (1-8) and candicanoside A (9), is reported. Key features include a one-flask CBS reduction/Brown hydroboration-oxidation, a SmI2-mediated intramolecular Reformatskii reaction, and an intramolecular transesterification. This synthesis provides a general strategy and key precursors for the collective synthesis of natural and designed saundersiosides. An efficient formal synthesis of candicanoside A is also achieved.
Assuntos
Ornithogalum/química , Sapogeninas/síntese química , Modelos Moleculares , Estrutura Molecular , Sapogeninas/química , Sapogeninas/isolamento & purificaçãoRESUMO
Based on the fact that timosaponin A-III (TA-III) exhibits potent cytotoxic effects and has been considered as a potential anti-tumor agent, a range of novel sarsasapogenin derivatives 1, 2a-2g, 3, 4, 5, 6a-6g have been synthesized by a simple and facile synthetic route. The in vitro cytotoxic activity of these synthetic compounds has been evaluated against ten human cancer cell lines. The pharmacological results showed that most of the sarsasapogenin derivatives displayed excellent selective cytotoxicity toward the cancer cell lines. An amino group at C-3 or C-26 position of the sapogenin had a profound influence on the cytotoxic activity. In particular, compound 6c exhibited significantly inhibitory activity against A375-S2 (IC50=0.56µM) and HT1080 (IC50=0.72µM) cells. However, introducing a bromo or morpholinyl substituent at the C-3 and C-26 position of the sapogenin generally rendered it inactive against the human cancer cell lines. This research provides a theoretical reference for the exploration of new anti-tumor drugs.
Assuntos
Antineoplásicos/farmacologia , Sapogeninas/farmacologia , Espirostanos/farmacologia , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Sapogeninas/síntese química , Espirostanos/síntese químicaRESUMO
Cycloastragenol (CAG) is an aglycone of astragaloside IV. It was first identified when screening Astragalus membranaceus extracts for active ingredients with antiaging properties. The present study demonstrates that CAG stimulates telomerase activity and cell proliferation in human neonatal keratinocytes. In particular, CAG promotes scratch wound closure of human neonatal keratinocyte monolayers in vitro. The distinct telomerase-activating property of CAG prompted evaluation of its potential application in the treatment of neurological disorders. Accordingly, CAG induced telomerase activity and cAMP response element binding (CREB) activation in PC12 cells and primary neurons. Blockade of CREB expression in neuronal cells by RNA interference reduced basal telomerase activity, and CAG was no longer efficacious in increasing telomerase activity. CAG treatment not only induced the expression of bcl2, a CREB-regulated gene, but also the expression of telomerase reverse transcriptase in primary cortical neurons. Interestingly, oral administration of CAG for 7 days attenuated depression-like behavior in experimental mice. In conclusion, CAG stimulates telomerase activity in human neonatal keratinocytes and rat neuronal cells, and induces CREB activation followed by tert and bcl2 expression. Furthermore, CAG may have a novel therapeutic role in depression.
Assuntos
Depressão/tratamento farmacológico , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Sapogeninas/administração & dosagem , Telomerase/metabolismo , Animais , Antidepressivos/administração & dosagem , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Humanos , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Camundongos , Fator de Crescimento Neural/metabolismo , Células PC12 , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Sapogeninas/síntese químicaRESUMO
Adenosine 5'-monophosphate-activated protein kinase (AMPK) has been demonstrated as a promising drug target due to its regulatory function in glucose and lipid metabolism. 20(S)-protopanoxadiol (PPD) was firstly identified from high throughput screening as a small molecule activator of AMPK subtype α2ß1γ1. In order to enhance its potency on AMPK, a series of PPD derivatives were synthesized and evaluated. Structure-activity relationship study showed that the amine derivatives at the 24-position (groups I-VI) can improve the potency (EC50: 0.7-2.3 µM) and efficacy (fold: 2.5-3.8). Among them, compounds 12 and 13 exhibited the best potency (EC50: 1.2 and 0.7 µM) and efficacy (fold: 3.7 and 3.8). Further study suggested the mechanism of AMPK activation may functioned at the allosteric position, resulting the inhibition of the lipid synthesis in HepG2 cell model.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Descoberta de Drogas , Ativadores de Enzimas/farmacologia , Sapogeninas/farmacologia , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Ativadores de Enzimas/síntese química , Ativadores de Enzimas/química , Células Hep G2 , Humanos , Conformação Molecular , Fosforilação/efeitos dos fármacos , Sapogeninas/síntese química , Sapogeninas/química , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
OBJECTIVE: To study the preparation of 20(S)-protopanaxadiol-phospholipid (20(S)-PPD) complex HAP assemblies. METHODS: 20(S)-PPD phospholipid complex was assembled with the drug carriers of HAP. Effects of technological factors on the assembled amount were investigated, including HAP species, phospholipid complex concentration, ratio of HAP and assembled liquid, and then the preparation technology of 20(S)-PPD phospholipid complex HAP assemblies was determined. RESULTS: The average quality of phospholipid complex assembled was 136. 26 mg/g,the average assembled rate was 5.3% for 20(S)-PPD phospholipid complex HAP assemblies prepared by the determined assembly process. FT-IR showed that 20(S)-PPD phospholipid complex was absorbed in the HAP assemblies, and the hydrogen-bonding effect was the main mechanism of HAP assemblies to assemble and adsorb phospholipid complex. The cumulative release rate in pH 7.4 phosphate buffer of the HAP assemblies indicated that the assemblies had the effect of sustained release. CONCLUSION: The phospholipid complex HAP assembles have the advantages of simple preparation process, and sustaining release effect, which can provide preliminary research foundation for research and development of 20(S)-PPD sustained-release preparations.
Assuntos
Portadores de Fármacos , Fosfolipídeos/química , Sapogeninas/síntese química , Adsorção , Preparações de Ação Retardada , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
Two unnatural steroid sapogenins bearing a furospirostane side chain were prepared starting from the readily available spirostane sapogenins, tigogenin and diosgenin following a synthetic protocol that included: (i) introduction of a carbonyl group at position C-23, (ii) diacetoxyiodobenzene-induced F-ring contraction and (iii) LiAlH4 reduction of the newly emerged methoxycarbonyl moiety. The structures of the new compounds were corroborated by NMR and X-ray studies.
Assuntos
Acetatos/química , Diosgenina/química , Iodobenzenos/química , Sapogeninas/síntese química , Espirostanos/química , Cristalografia por Raios X , Hidrólise , Espectroscopia de Ressonância Magnética , Conformação MolecularRESUMO
The synthesis of glucosamine derivatives of the steroidal sapogenins diosgenin and hecogenin using the N-phthaloyl protected trichloroacetimidate of d-glucosamine as donor and TMSOTf as promoter is reported. The corresponding glycoconjugates were transformed into their acetamido derivatives and the hydrochloride salt (from diosgenin) and tested against HeLa, CaSki, and ViBo cervicouterine cancer cells. These compounds showed low cytotoxicity values on tumor cells and human lymphocytes, indicating that the main cell death process is presumably not necrosis. Significantly, the antiproliferative activity of these compounds on tumor cells did not affect the proliferative potential of peripheral blood lymphocytes.