Arylsulfonamide derivatives of (aryloxy)ethyl pyrrolidines and piperidines as α1-adrenergic receptor antagonist with uro-selective activity

A series of arylsulfonamide derivatives of (aryloxy)ethyl pyrrolidines and piperidines was synthesized to develop new α₁-adrenoceptor antagonists with uroselective profile. Biological evaluation for α₁- and α₂-adrenorecepor showed that tested compounds 13–37 displayed high-to-moderate affinity for the α₁-adrenoceptor (K_i = 34–348 nM) and moderate selectivity over α₂-receptor subtype. Compounds with highest affinity and selectivity for α₁-adrenoceptor were evaluated in vitro for their intrinsic activity toward α_1A- and α_1B-adrenoceptor subtypes. All compounds behaved as antagonists at both α₁-adrenoceptor subtypes, displaying 2- to 6-fold functional preference to α_1A-subtype. Among them, N-{1-[2-(2-methoxyphenoxy)ethyl]piperidin-4-yl}isoquinoline-4-sulfonamide (25) and 3-chloro-2-fluoro-N-{[1-(2-(2-isopropoxyphenoxy)ethyl)piperidin-4-yl]methyl}benzene sulfonamide (34) displayed the highest preference to α_1A-adrenoceptor. Finally, compounds 25 and 34 (2–5 mg/kg, iv), in contrast to tamsulosin (1–2 mg/kg, iv), did not significantly decrease systolic and diastolic blood pressure in normotensive anesthetized rats to determine their influence on blood pressure.     

Design,synthesis, docking study, α-glucosidase inhibition,and cytotoxic activities of acridine linked to thioacetamides as novel agents in treatment of type 2 diabetes

A novel series of acridine linked to thioacetamides 9a–o were synthesized and evaluated for their α-glucosidase inhibitory and cytotoxic activities. All the synthesized compounds exhibited excellent α-glucosidase inhibitory activity in the range of IC₅₀ = 80.0 ± 2.0–383.1 ± 2.0 µM against yeast α-glucosidase, when compared to the standard drug acarbose (IC₅₀ = 750.0 ± 1.5 µM). Among the synthesized compounds, 2-((6-chloro-2-methoxyacridin-9-yl)thio)-N-(p-tolyl) acetamide 9b displayed the highest α-glucosidase inhibitory activity (IC₅₀ = 80.0 ± 2.0 μM). The in vitro cytotoxic assay of compounds 9a–o against MCF-7 cell line revealed that only the compounds 9d, 9c, and 9n exhibited cytotoxic activity. Cytotoxic compounds 9d, 9c, and 9n did not show cytotoxic activity against the normal human cell lines HDF. Kinetic study revealed that the most potent compound 9b is a competitive inhibitor with a K_i of 85 μM. Furthermore, the interaction modes of the most potent compounds 9b and 9f with α-glucosidase were evaluated through the molecular docking studies.     

Design,synthesis and molecular modeling of new 4-phenylcoumarin derivatives as tubulin polymerization inhibitors targeting MCF-7 breast cancer cells

A new set of 4-phenylcoumarin derivatives was designed and synthesized aiming to introduce new tubulin polymerization inhibitors as anti-breast cancer candidates. All the target compounds were evaluated for their cytotoxic effects against MCF-7 cell line, where compounds 2f, 3a, 3b, 3f, 7a and 7b, showed higher cytotoxic effect (IC₅₀?=?4.3–21.2?μg/mL) than the reference drug doxorubicin (IC₅₀?=?26.1?μg/mL), additionally, compounds 1 and 6b exhibited the same potency as doxorubicin (IC₅₀?=?25.2 and 28.0?μg/mL, respectively). The thiazolidinone derivatives 3a, 3b and 3f with potent and selective anticancer effects towards MCF-7 cells (IC₅₀?=?11.1, 16.7 and 21.2?μg/mL) were further assessed for tubulin polymerization inhibition effects which showed that the three compounds were potent tubulin polymerization suppressors with IC₅₀ values of 9.37, 2.89 and 6.13?μM, respectively, compared to the reference drug colchicine (IC₅₀?=?6.93?μM). The mechanistic effects on cell cycle progression and induction of apoptosis in MCF-7 cells were determined for compound 3a due to its potent and selective cytotoxic effects in addition to its promising tubulin polymerization inhibition potency. The results revealed that compound 3a induced cell cycle cessation at G2/M phase and accumulation of cells in pre-G1 phase and prevented its mitotic cycle, in addition to its activation of caspase-7 mediating apoptosis of MCF-7 cells. Molecular modeling studies for compounds 3a, 3b and 3f were carried out on tubulin crystallography, the results indicated that the compounds showed binding mode similar to the co-crystalized ligand; colchicine. Moreover, pharmacophore constructed models and docking studies revealed that thiazolidinone, acetamide and coumarin moieties are crucial for the activity. Molecular dynamics (MD) studies were carried out for the three compounds over 100?ps. MD results of compound 3a showed that it reached the stable state after 30?ps which was in agreement with the calculated potential and kinetic energy of compound 3a.     

Chronic ethanol attenuates centrally-mediated hypotension elicited via α2-adrenergic,but not I1-imidazoline,receptor activation in female rats

AimsThis study dealt with the effect of chronic ethanol administration on hemodynamic responses elicited by α₂-adrenergic (α-methyldopa) or I₁-imidazoline (rilmenidine) receptor activation in telemetered female rats.Main methodsThe effects of α-methyldopa or rilmenidine on blood pressure (BP), heart rate (HR) and their variability were investigated in rats that received liquid diet without or with ethanol (5% w/v) for 12 weeks. To evaluate the effect of each drug on cardiovascular autonomic control (BP and HR variability) in the absence or presence of ethanol, three time-domain indices of hemodynamic variability were measured: (i) standard deviation of mean arterial pressure (SDMAP), (ii) standard deviation of beat-to-beat intervals, and (iii) root mean square of successive differences in R–R intervals.Key findingsIn liquid diet-fed control rats, i.p. rilmenidine (600 µg/kg) or α-methyldopa (100 mg/kg) reduced BP along with decreases and increases, respectively, in HR. Both drugs had no effect on HR variability but reduced BP variability (SDMAP), suggesting a reduced vasomotor sympathetic tone. Ethanol feeding attenuated reductions in BP and SDMAP evoked by α-methyldopa but not by rilmenidine.SignificanceWe conclude that chronic ethanol preferentially compromises α₂- but not I₁-receptor-mediated hypotension in female rats probably via modulation of vasomotor sympathetic activity. These findings highlight the adequacy of rilmenidine use to lower BP in hypertensive alcoholic females.     

Design,synthesis and antitumour and anti-angiogenesis evaluation of 22 moscatilin derivatives

Two series of moscatilin derivatives were designed, synthesized and evaluated as anti-tumor and anti-angiogenesis agents. Most of these compounds showed moderate-to-obvious cytotoxicity against five cancer cell lines (A549, HepG2, MDA-MB-231, MKN-45, HCT116). Among these cell lines, compounds had obvious effects on HCT116. Especially for 8Ae, the IC₅₀ was low to 0.25 μM. 8Ae can inhibit the viability and induce the apoptosis of HCT116 cells but exhibit no cytotoxic activity in noncancerous NCM460 colon cells. 8Ae can also arrest the G2/M cell cycle in HCT116 cells by inhibiting the α-tubulin expression. Zebrafish bioassay-guided screen showed the 22 moscatilin derivatives had potent anti-angiogenic activities and compound 8Ae had better activities than positive compound. Molecular docking indicated 8Ae interacted with tubulin at the affinity of −7.2 Kcal/mol. In conclusion, compound 8Ae was a potential antitumor and anti-angiogenesis candidate for further development.     

3-[(Imidazolidin-2-yl)imino]indazole ligands with selectivity for the α(2)-adrenoceptor compared to the imidazoline I(1) receptor

A series of 3-[(4,5-dihydroimidazolidin-2-yl)imino]indazoles has been synthesized as positional analogues of marsanidine, a highly selective ??₂-adrenoceptor ligand. Parent compound 4a and its 4-chloro (4c) and 4-methyl (4d) derivatives display ??₂-adrenoceptor affinity at nanomolar concentrations (K_i = 39.4, 15.9 and 22.6 nM, respectively) and relatively high ??₂/I₁ selectivity ratios of 82, 115 and 690, respectively. Evidence was obtained that these compounds act as partial agonists at ??_2A-adrenoceptors. Compound 4d with intrinsic activity comparable with that of marsanidine, but lower than that of clonidine, elicited pronounced cardiovascular effects in anesthetized rats at doses as low as 0.01 mg/kg iv     

Synthesis and topoisomerase II inhibitory and cytotoxic activity of oxiranylmethoxy- and thiiranylmethoxy-chalcone derivatives

In order to find potential anticancer drug candidate targeting topoisomerases enzyme, we have designed and synthesized oxiranylmethoxy- and thiiranylmethoxy-retrochalcone derivatives and evaluated their pharmacological activity including topoisomerases inhibitory and cytotoxic activity. Of the compounds prepared compound 25 showed comparable or better cytotoxic activity against cancer cell lines tested. Compound 25 inhibited MCF7 (IC₅₀: 0.49 ± 0.21 μM) and HCT15 (IC₅₀: 0.23 ± 0.02 μM) carcinoma cell growth more efficiently than references. In the topoisomerases inhibition test, all the compounds were inactive to topoisomerase I but moderate inhibitors to topoisomerase II enzyme. Especially, compound 25 inhibited topoisomerase II activity with comparable extent to etoposide at 100 μM concentrations. Correlation between cytotoxicity and topoisomerase II inhibitory activity implies that compound 25 can be a possible lead compound for anticancer drug impeding the topoisomerase II function.     

Cytotoxic diterpenoids as potential anticancer agents from the twigs of Casearia kurzii

A search for bioactive natural products as anticancer lead compounds has led to the isolation of five new clerodane diterpenoids (1–5) from the twigs of Casearia kurzii. Their structures were elucidated by extensive analysis of their NMR, IR, and HRESIMS data, and the absolute configurations were determined by experimental and calculated electronic circular dichroism (ECD) data analysis. The isolates were biologically evaluated and showed cytotoxic activities toward human lung cancer cells (A549), human cervical cancer cells (HeLa), and human hepatocellular carcinoma cells (HepG2). The most active compound (5) with an IC₅₀ value of 5.3 μM against HeLa cells, was found to induce apoptosis and arrest the HeLa cell cycle at G0/G1 stage to exert cytotoxic effects.     

Search for influence of spatial properties on affinity at α1-adrenoceptor subtypes for phenylpiperazine derivatives of phenytoin

A series of phenylpiperazine derivatives of phenytoin was evaluated for their affinity at α₁-adrenoceptor subtypes in functional bioassays (rat tail artery: α_1A and/or α_1B; guinea pig spleen: α_1B; rat aorta: α_1D). The most potent compounds at α_1A-, α_1B- and α_1D-adrenoceptors, 11, 18 and 8, showed affinities in the submicromolar range. The role of a hydrogen bond donor group for affinity and selectivity at α_1B-adrenoceptors, postulated by Bremner’s pharmacophore model, was confirmed by functional and molecular modelling studies.     

Apoptotic induction mediated p53 mechanism and Caspase-3 activity by novel promising cyanoacrylamide derivatives in breast carcinoma

New cyanoacrylamide derivatives were theoretically examined for their binding abilities to a protein model of apoptosis inhibitor proteins x-IAP and c-IAP1 using molecular modeling. The two compounds 5a and 5b proved promising IAP antagonists, where they have good binding affinity toward the selected active domains. Anticancer activity of all derivatives was performed on different human cancer cell lines (HCT116, Caco₂, and MCF7) as well as normal line (HBF4). Data revealed that breast carcinoma was more sensitive to the novel compounds than other lines especially compounds 5a and 5b, but all derivatives lost their cytotoxic effect in case of Caco2 cell line and they showed low cytotoxic effect toward HCT116 cells except compound 3. The flow cytometric analysis revealed that the two compounds 5a and 5b induced apoptosis to 46.5% and 54.8% respectively, relative to control 8.06%. In addition, PCR results indicated that the two compounds 5a and 5b induced the expression of p53 gene and decreased induction of BCL2 (anti-apoptotic gene), while the two compounds have no effect on the protein expression of Caspase-9. By monitoring the presence of Caspase-3 which was a mean to detect apoptotic death in breast carcinoma, the two compounds have stimulated the induction of apoptosis by increasing the production of Caspase-3 protein. Finally, it was concluded that the two compounds 5b and 5a have the most promising anti-cancer activity against human breast carcinoma (MCF7), and it is believed that the anticancer activities of these two compounds were due to being the most effective in the inhibition of a member of IAPs groups, leading to activation of p53 gene and the Caspase-3 dependent apoptosis.     

Pharmacological properties and predicted binding mode of arylmethylene quinuclidine-like derivatives at the α3β4 nicotinic acetylcholine receptor (nAChR)

We have carried out a pharmacological evaluation of arylmethylene quinuclidine derivatives interactions with human α3β4 nAChRs subtype, using cell-based receptor binding, calcium-influx, electrophysiological patch-clamp assays and molecular modeling techniques. We have found that the compounds bind competitively to the α3β4 receptor with micromolar affinities and some of the compounds behave as non-competitive antagonists (compounds 1, 2 and 3), displaying submicromolar IC₅₀ values. These evidences suggest a mixed mode of action for these compounds, having interactions at the orthosteric site and more pronounced interactions at an allosteric site to block agonist effects. One of the compounds, 1-benzyl-3-(diphenylmethylene)-1-azoniabicyclo[2.2.2]octane chloride (compound 3), exhibited poorly reversible use-dependent block of α3β4 channels. We also found that removal of a phenyl group from compound 1 confers a partial agonism to the derived analog (compound 6). Introducing a hydrogen-bond acceptor into the 3-benzylidene quinuclidine derivative (compound 7) increases agonism potency at the α3β4 receptor subtype. Docking into the orthosteric binding site of a α3β4 protein structure derived by comparative modeling accurately predicted the experimentally-observed trend in binding affinity. Results supported the notion that binding requires a hydrogen bond formation between the ligand basic nitrogen and the backbone carbonyl oxygen atom of the conserved Trp-149.     

Dual EGFR/HER2 inhibitors and apoptosis inducers: New benzo[g]quinazoline derivatives bearing benzenesulfonamide as anticancer and radiosensitizers

Dual targeting of EGFR and HER2 is a proven anticancer strategy for the treatment of solid tumors. An array of new N-substituted-2-(4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydrobenzo[g]quinazolin-2-ylthio) acetamides 5–18 were designed and synthesized from the starting compound 4-(2-mercapto-4-oxobenzo[g]quinazolin-3(4H)-yl) benzenesulfonamide 4. The targeted compounds were screened for their cytotoxic activity against MDA-MB-231 breast cancer cell line. The IC₅₀ of all the compounds were in the range of 0.36–40.90 µM. The percentage inhibition towards EGFR was measured and found to be in the range of 63.00–16.90 %. The most potent compounds 5, 9, 15, 17 and 18 were further screened for their activity against both EGFR and HER2 receptors. The compounds showed IC₅₀ in the range of 0.64–1.81 µM for EGFR and 1.13–2.21 µM for HER2, in comparison to erlotinib, the reference drug. Compound 17, the most potent towards EGFR in this series, undergoes cell cycle analysis and was found to arrest the cycle at the G2/M phase. Measurement of the cytotoxicity of compound 17 against normal breast cell line showed mild cytotoxic activity. The most potent compounds were subjected to a single dose of 8 Gy of γ-radiation and the cytotoxicity of the tested compounds was found to increase after irradiation, thus proving the synergistic effect of γ-irradiation. Molecular docking was adopted for all the synthesized compounds to confirm their mechanism of action.     

Design,synthesis, in silico and in vitro evaluation of thiophene derivatives: A potent tyrosine phosphatase 1B inhibitor and anticancer activity

A series of novel methyl 4-(4-amidoaryl)-3-methoxythiophene-2-carboxylate derivatives were designed against the active site of protein tyrosine phosphatise 1B (PTP1B) enzyme using MOE.2008.10. These molecules are also subjected for in silico toxicity prediction studies and considering their corresponding drug scores, it implied that, the molecules are promising as anticancer agents. The designed compounds were synthesized by using suitable methods and characterized. They were subjected to inhibitory activity against PTP1B and in vitro anticancer activity by MTT assay. Most of the tested compounds showed potent inhibitory activity against PTP1B, among the compounds tested, compound 5b exhibited the highest activity (IC₅₀ = 5.25 µM) and remarkable cytotoxic activity at 0.09 µM of IC₅₀ against the MCF-7 cell line. In addition to this, compound 5c also showed potential anticancer activity at 2.22 µM of IC₅₀ against MCF-7 and 0.72 µM against HepG2 cell lines as well as PTP1B inhibitory activity at IC₅₀ of 6.37 µM.     

Synthesis and biological evaluation of some novel thiobenzimidazole derivatives as anti-renal cancer agents through inhibition of c-MET kinase

Benzimidazole is an interesting scaffold constituting a main core in many anticancer agents against variable cell lines as Carbendazim (I) and Nocodazole (II). Accordingly, eighteen compounds of 2-((1H-benzoimidazol-2-yl)thio)-1-(aryl/heteroaryl)ethan-1-ones, in their sulfate salt and free forms, were designed and investigated as anticancer agents. In vitro preliminary screening of selected compounds by the National Cancer Institute (NCI) on a panel of 60 cell lines revealed renal cancer cell line (A498) as the most vulnerable cell line; accordingly, IC₅₀ values against A498 cell line were determined for compounds with the best results. The best inhibitory activity was for compound 4a with (IC₅₀ = 6.97 µM) compared to sunitinib as a reference drug (IC₅₀ = 6.99 µM). Compound 4a was further subjected to cell cycle analysis that indicated the decrease in cell population in the G2/M phase when compared to the untreated control cells. In addition, it showed significant increase in the late apoptosis in Annexin-V FTIC study compared to the control cells. An enzymatic inhibitory study on compound 4a against c-Met and MAP kinases revealed its better activity against c-Met kinase with (IC₅₀ = 0.27 µM) compared to sunitinib (IC₅₀ = 0.18 µM). Molecular docking study was conducted to reveal the interactions of compound 4a in the active site of c-Met kinase. Computational ADME study was performed to insure that compound 4a has proper pharmacokinetic and drug-likeness properties.     

Development of CNS multi-receptor ligands: Modification of known D2 pharmacophores

Several known D₂ pharmacophores have been explored as templates for identifying ligands with multiple binding affinities at dopamine and serotonin receptors considered as clinically relevant receptors in the treatment of neuropsychiatric diseases. This approach has resulted in the identification of ligands that target multiple CNS receptors while avoiding others associated with deleterious effects. In particular, compounds 11, 15 and 22 may have potential for further development as antipsychotic agents as they favorably interact with the clinically relevant receptors including D₂R, 5-HT_1AR, and 5-HT₇R. We have also identified the pair of compounds 11 and 10 as high affinity D₂R ligands with and without SERT binding affinities, respectively. These differential binding profiles endow the pair with the potential for evaluating SERT contributions to antipsychotic drug activity in animal behavioral models. In addition, compound 11 has no significant affinity for 5-HT_2CR and binds only moderately to the H₁R, suggesting it may not induce weight gain or sedation when used clinically. Taken together, compound 11 displays an interesting pharmacological profile that necessitates the evaluation of its functional and in vivo effects in animal models which are currently ongoing.     

New imidazoline/α(2)-adrenoceptors affecting compounds-4(5)-(2-aminoethyl)imidazoline (dihydrohistamine) derivatives. Synthesis and receptor affinity studies

Compilation of agmatine structure and imidazoline moiety leads to a new group of imidazoline/??₂-adrenoceptor ligands, 4(5)-(2-aminoethyl)imidazoline derivatives. In this study the exploration of previously unknown 4(5)-(2-aminoethyl)imidazolines including the analogues of reported imidazoline and ??₂-aderenoceptors ligands: clonidine, rilmenidine, idazoxan, efaroxan, antazoline, tracizoline is described. The synthesis of a variety of novel 4(5)-(2-aminoethyl)imidazolines and their I₁, I₂, ??₂-adrenoceptors affinities are reported.     

EGFR inhibitors and apoptotic inducers: Design,synthesis, anticancer activity and docking studies of novel xanthine derivatives carrying chalcone moiety as hybrid molecules

One of the helpful ways to improve the effectiveness of anticancer agents and weaken drug resistance is to use hybrid molecules. therefore, the current study intended to introduce 20 novel xanthine/chalcone hybrids 9–28 of promising anticancer activity. Compounds 10, 11, 13, 14, 16, 20 and 23 exhibited potent inhibition of cancer cells growth with IC₅₀ ranging from 1.0 ± 0.1 to 3.5 ± 0.4 μM compared to doxorubicin with IC₅₀ ranging from 0.90 ± 0.62 to 1.41 ± 0.58 μM and that compounds 11 and 16 were the best. To verify the mechanism of their anticancer activity, compounds 10, 11, 13, 14, 16, 20 and 23 were evaluated for their EGFR inhibitory effect. The study results revealed that compound 11 showed IC₅₀ = 0.3 µM on the target enzyme which is more potent than staurosporine reference drug (IC₅₀ = 0.4 µM). Accordingly, the apoptotic effect of the most potent compounds 11 was extensively investigated and showed a marked increase in Bax level up to 29 folds, and down-regulation in Bcl2 to 0.28 fold, in comparison to the control. Furthermore, the effect of compound 11 on Caspases 3 and 8 was evaluated and was found to increase their levels by 8 and 14 folds, respectively. Also, the effect of compound 11 on the cell cycle and its cytotoxic effect were examined. Moreover, a molecular docking study was adopted to confirm mechanism of action.     

Design,synthesis and biological evaluation of novel hydrogen sulfide releasing capsaicin derivatives

Capsaicin (CAP), the prototypical TRPV1 agonist, is the major active component in chili peppers with health-promoting benefits. However, its use is limited by the low bioavailability and irritating quality. In this study, for improving the activity of CAP and alleviating its irritating effects, a series of H₂S-releasing CAPs were designed and synthesized by combining capsaicin and dihydro capsaicin with various hydrogen sulfide donors. The resulting compounds were evaluated their TRPV1 agonist activity, analgesic activity, anticancer activities, H₂S-releasing ability, and gastric mucosa irritation. Biological evaluation indicated that the most active compound B₉, containing 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione moiety as H₂S donor, had better analgesic activity and displayed more potent cytotoxic effects on the test cell lines than the lead compound CAP. Furthermore, the preferred compound, B₉ reduced rat gastric mucosa irritation caused by CAP. Notably, the improved properties of this derivative are associated with its H₂S-releasing capability.     

The identification of 7-[(R)-2-((1S,2S)-2-benzyloxycyclopentylamino)-1-hydroxyethyl]-4-hydroxybenzothiazolone as an inhaled long-acting β2-adrenoceptor agonist

The optimisation of two series of 4-hydroxybenzothiazolone derived β₂-adrenoceptor agonists, bearing α-substituted cyclopentyl and β-phenethyl amino-substituents, as inhaled long-acting bronchodilators is described. Analogues were selected for synthesis using a lipophilicity based hypothesis to achieve the targeted rapid onset of action in combination with a long duration of action. The profiling of the two series led to identification of the α-substituted cyclopentyl analogue 2 as the optimal compound with a comparable profile to the inhaled once-daily long-acting β₂-adrenoceptor agonist indacaterol. On the basis of these data 2 was promoted as the backup development candidate to indacaterol from the Novartis LABA project.     

Synthesis and evaluation of 5-(1H-indol-3-yl)-N-aryl-1,3,4-oxadiazol-2-amines as Bcl-2 inhibitory anticancer agents

A series of 5-(1H-indol-3-yl)-N-aryl-1,3,4-oxadiazol-2-amines 8a–j has been designed, synthesized and tested in vitro as potential pro-apoptotic Bcl-2-inhibitory anticancer agents based on our previous lead compound 8a. Synthesis of the target compounds was readily accomplished through a cyclisation reaction between indole-3-carboxylic acid hydrazide (5) and substituted isothiocyanates 6a–j, followed by oxidative cyclodesulfurization of the corresponding thiosemicarbazide 7a–j using 1,3-dibromo-5,5-dimethylhydantoin. Active compounds of the series 8a–j were found to have sub-micromolar IC₅₀ values selectively in Bcl-2 expressing human cancer cell lines; notably the 2-nitrophenyl analogue 8a was found to exhibit potent activity, and compounds 8a and 8e possessed comparable Bcl-2 binding affinity (ELISA assay) to the established natural product-based Bcl-2 inhibitor, gossypol. Molecular modeling studies helped to further rationalise anti-apoptotic Bcl-2 binding, and identified compounds 8a and 8e as candidates for further development as Bcl-2 inhibitory anticancer agents.