Synthesis and in vitro Evaluation of 3H‐Pyrrolo[3,2‐f]quinolin‐9‐one Derivatives That Show Potent and Selective Anti‐leukemic Activity

A series of new substituted 7‐phenyl‐3H‐pyrrolo[3,2‐f]quinolin‐9‐ones were synthesized and evaluated for their antiproliferative activity. The most active derivatives showed high selectivity against human leukemia cell lines and potently inhibited their growth, with GI₅₀ values in the nanomolar range. The active compounds strongly blocked tubulin assembly and colchicine binding to tubulin. Their activities were equal to or greater than that of the reference compound combretastatin A‐4. Flow cytometry studies showed that the two most active compounds arrested Jurkat cells in the G₂/M cell‐cycle phase in a concentration‐dependent manner. This effect was associated with apoptosis, mitochondrial depolarization, generation of reactive oxygen species, activation of caspase‐3, and cleavage of the enzyme poly(ADP‐ribose) polymerase.     

Identification of Hck Inhibitors As Hits for the Development of Antileukemia and Anti‐HIV Agents

Hematopoietic cell kinase (Hck) is a member of the Src family of non‐receptor protein tyrosine kinases. High levels of Hck are associated with drug resistance in chronic myeloid leukemia. Furthermore, Hck activity has been connected with HIV‐1. Herein, structure‐based drug design efforts were aimed at identifying novel Hck inhibitors. First, an in‐house library of pyrazolo[3,4‐d]pyrimidine derivatives, which were previously shown to be dual Abl and c‐Src inhibitors, was analyzed by docking studies within the ATP binding site of Hck to select the best candidates to be tested in a cell‐free assay. Next, the same computational protocol was applied to screen a database of commercially available compounds. As a result, most of the selected compounds were found active against Hck, with K_i values ranging from 0.14 to 18.4 μM , confirming the suitability of the computational approach adopted. Furthermore, selected compounds showed an interesting antiproliferative activity profile against the human leukemia cell line KU‐812, and one compound was found to block HIV‐1 replication at sub‐toxic concentrations.     

Design,Synthesis, and SAR of Naphthyl‐Substituted Diarylpyrimidines as Non‐Nucleoside Inhibitors of HIV‐1 Reverse Transcriptase

A series of 38 2‐naphthyl‐substituted diarylpyrimidine (DAPY) analogues, characterized by various substitution patterns on the pyrimidine and naphthalene rings, was synthesized in a straightforward fashion by means of parallel synthesis and evaluated as inhibitors of the HIV‐1 wild‐type and double mutant (K103N+Y181C) strains. Most of the compounds displayed strong activity against wild‐type HIV‐1. The most active compound, with a cyano group at position C6 on the naphthalene ring, exhibited activity against wild‐type HIV‐1 with an EC₅₀ value of 0.002 μM and against the double mutant strain with an EC₅₀ value of 0.24 μM ; the selectivity index (SI) against wild‐type is >180 000, the highest SI value among DAPY analogues. The structure–activity relationship (SAR) of the newly synthesized DAPYs is presented herein.     

Toxicity of three F‐substituent aromatics in anaerobic systems

BACKGROUND: The commercial use of organofluorine compounds has dramatically increased over the past few years. However, little information has been reported on the potential toxicity of organofluorine compounds to anaerobic digestion processes. In this work, the effects of 4‐fluorophenol (p‐FP), 4‐fluorobenzoic acid (p‐FB) and 4‐fluoroaniline (p‐FA) on methanogenesis and biodegradability were evaluated using sucrose‐fed systems. RESULTS: The anaerobic biodegradation of three test compounds was not observed in the study. Adsorption of p‐FP, p‐FB and p‐FA to the sludge fitted the linear model well (r² > 0.94). The partition coefficient K_d was 25 L kg^?1 for p‐FP, 16 L kg^?1 for p‐FB and 26 L kg^?1 for p‐FA. Both methanogensis and hydrolysis acidification were inhibited in the presence of three test compounds. The half maximal inhibitory concentrations (IC₅₀s) of methanogenic activity were 339, 1390 and 1907 mg L^?1 for p‐FP, p‐FB and p‐FA, respectively. A significant linear correlation (R² = 0.99, P < 0.05) was obtained between the half maximal inhibitory concentrations and the most negative atomic charges of molecules (q^?) of the three F‐substituent aromatics. CONCLUSIONS: Three F‐substituent aromatics had specific effects on methanogensis, hydrolysis acidification and syntrophic cooperation in anaerobic systems. Copyright © 2012 Society of Chemical Industry     

Synthetic and Biological Studies of Tubulin Targeting C2‐Substituted 7‐Deazahypoxanthines Derived from Marine Alkaloid Rigidins

C2‐aryl‐ and C2‐alkyl‐7‐deazahypoxanthines as analogues of marine alkaloid rigidins were prepared utilizing novel synthetic methods developed for the construction of the pyrrolo[2,3‐d]pyrimidine ring system. The new compounds exhibited sub‐micromolar to nanomolar antiproliferative potencies against a panel of cell lines including in vitro models for drug‐resistant tumors, such as glioblastoma, melanoma and non‐small‐cell lung cancer. A selected representative C2‐methyl‐7‐deazahypoxanthine was found to inhibit microtubule dynamics in cancer cells, lending evidence for tubulin targeting as a mode of action for these compounds in cancer cells. The results of the docking studies utilizing the colchicine site on β‐tubulin were consistent with the observed structure–activity relationship data, including an important finding that derivatization at C2 with linear alkyl groups leads to the retention of activity, thus permitting the attachment of a biotin‐containing linker for the subsequent proteomics assays. Because many microtubule‐targeting compounds are successfully used to fight cancer in the clinic, the reported antitubulin rigidin analogues have significant potential as new anticancer agents.     

Design and Synthesis of N‐Acylated Aza‐Goniothalamin Derivatives and Evaluation of Their in vitro and in vivo Antitumor Activity

Herein we describe the synthesis of a focused library of compounds based on the structure of goniothalamin ( 1 ) and the evaluation of the potential antitumor activity of the compounds. N‐Acylation of aza‐goniothalamin ( 2 ) restored the in vitro antiproliferative activity of this family of compounds. 1‐(E)‐But‐2‐enoyl‐6‐styryl‐5,6‐dihydropyridin‐2(1H)‐one ( 18 ) displayed enhanced antiproliferative activity. Both goniothalamin ( 1 ) and derivative 18 led to reactive oxygen species generation in PC‐3 cells, which was probably a signal for caspase‐dependent apoptosis. Treatment with derivative 18 promoted Annexin V/7‐aminoactinomycin D double staining, which indicated apoptosis, and also led to G₂/M cell‐cycle arrest. In vivo studies in Ehrlich ascitic and solid tumor models confirmed the antitumor activity of goniothalamin ( 1 ), without signs of toxicity. However, derivative 18 exhibited an unexpectedly lower in vivo antitumor activity, despite the treatments being administered at the same site of inoculation. Contrary to its in vitro profile, aza‐goniothalamin ( 2 ) inhibited Ehrlich tumor growth, both on the ascitic and solid forms. Our findings highlight the importance of in vivo studies in the search for new candidates for cancer treatment.     

Syntheses and biological activities of novel diheterocyclic compounds containing 1,2,4‐triazolo[1,5‐a]pyrimidine and 1,3,4‐oxadiazole

In a search for novel agrochemicals with high activity and low toxicity, a series of diheterocyclic compounds containing 1,2,4‐triazolo[1,5‐a]pyrimidine and 1,3,4‐oxadiazole rings were designed and synthesized by a four‐step synthetic route starting from 2‐mercapto‐5,7‐dimethyl‐1,2,4‐triazolo[1,5‐a]pyrimidine. The structures of all the compounds synthesized were confirmed by ¹H NMR, mass spectroscopy and elemental analysis. The preliminary bioassay against Brassica campestris L and Echinochloa crusgalli Beavu indicated that the title compounds displayed herbicidal activity at the concentration of 100 ppm and that compounds 5a (R = CH₃), 5d (R = C₂H₅) and 5f (R = i‐Bu) were found to have particularly high activities. In addition, the results of an in vivo test at a concentration of 50 ppm showed that all the compounds prepared were highly active against Rhizoctonia slain, but not active against Fusarium oxysporum, Gibberella zeave and Phoma sparagi. A further in vivo test showed that compound 5j possessed better fungicidal activity against Rhizoctonia solani at a concentration of 200 ppm than Carbendazim and Validamycin A, which are well known for their fungicidal activity against Rhizoctonia solani. To our knowledge, this is the first report that 1,2,4‐triazolo[1,5‐a]pyrimidine derivatives display fungicidal activity against Rhizoctonia solani. © 2001 Society of Chemical Industry     

Synthesis and anti-HIV activity of aryl-2-[(4-cyanophenyl)amino]-4-pyrimidinone hydrazones as potent non-nucleoside reverse transcriptase inhibitors

A series of novel diarylpyrimidines (DAPYs) with a ketone hydrazone substituent on the methylene linker between the pyrimidine nucleus and the aryl moiety at the C‐4 position were synthesized, and their antiviral activity against human immunodeficiency virus (HIV)‐1 in MT‐4 cells was evaluated. Most compounds of this class exhibited excellent activity against wild‐type HIV‐1, with EC₅₀ values in the range of 1.7–13.2 nM . Of these compounds, 2‐bromophenyl‐2‐[(4‐cyanophenyl)amino]‐4‐pyrimidinone hydrazone ( 9 k ) displayed the most potent anti‐HIV‐1 activity (EC₅₀=1.7±0.6 nM ), with excellent selectivity for infected over uninfected cells (SI=5762). In addition, the 4‐methyl phenyl analogue 9 d (EC₅₀=2.4±0.2 nM , SI=18461) showed broad spectrum HIV inhibitory activity, with EC₅₀ values of 2.4±0.2 nM against wild‐type HIV‐1, 5.3±0.4 μM against HIV‐1 double‐mutated strain RES056 (K103N+Y181C), and 5.5 μM against HIV‐2 ROD strain. Furthermore, structure–activity relationship (SAR) data and molecular modeling results for these compounds are also discussed.     

Synthesis and spectroelectrochemistry of dithieno(3,2‐b:2′,3′‐d)pyrrole derivatives

New π‐conjugated polymers containing dithieno(3,2‐b:2′,3′‐d)pyrrole (DTP) were successfully synthesized via electropolymerization. The effect of structural differences on the electrochemical and optoelectronic properties of the 4‐[4H‐dithieno(3,2‐b:2′,3′‐d)pyrrol‐4‐yl]aniline (DTP–aryl–NH₂), 10‐[4H‐dithiyeno(3,2‐b:2′,3′‐d)pirol‐4‐il]dekan‐1‐amine (DTP–alkyl–NH₂), and 1,10‐bis[4H‐dithieno(3,2‐b:2′,3′‐d)pyrrol‐4‐yl] decane (DTP–alkyl–DTP) were investigated. The corresponding polymers were characterized by cyclic voltammetry, NMR (¹H‐NMR and ¹³C‐NMR), and ultraviolet–visible spectroscopy. Changes in the electronic nature of the functional groups led to variations in the electrochemical properties of the π‐conjugated systems. The electroactive polymer films revealed redox couples and exhibited electrochromic behavior. The replacement of the DTP–alkyl–DTP unit with DTP–aryl–NH₂ and DTP–alkyl–NH₂ resulted in a lower oxidation potential. Both the poly(10‐(4H‐Dithiyeno[3,2‐b:2′,3′‐d]pirol‐4‐il)dekan‐1‐amin) (poly(DTP–alkyl–NH₂)) and poly(1,10‐bis(4H‐dithieno[3,2‐b:2′,3′‐d]pyrrol‐4‐yl) decane) (poly(DTP–alkyl–DTP)) films showed multicolor electrochromism and also fast switching times (<1 s) in the visible and near infrared regions. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40701.     

Biodistribution and photodynamic efficacy of a water-soluble, stable, halogenated bacteriochlorin against melanoma

The in vitro phototoxicity of a photostable, synthetic, water‐soluble, halogenated bacteriochlorin, 5,10,15,20‐tetrakis(2‐chloro‐5‐sulfophenyl)bacteriochlorin (TCPBSO₃H), toward mouse melanoma (S91) cells is ～60‐fold higher than that of the analogous porphyrin, and is associated with very weak toxicity in the dark; 90 % of S91 cells were killed in response to a light dose of 0.26 J cm^?2 in the presence of [TCPBSO₃H]=5 μM . In vivo toxicity toward DBA mice is very low, even at doses of 20 mg kg^?1. In vivo pharmacokinetics and biodistribution of TCPBSO₃H were studied in DBA mice with S91 tumors; 24 h after intraperitoneal injection of 10 mg kg^?1, TCPBSO₃H demonstrated preferential accumulation in S91 mouse melanoma, with tumor‐to‐normal tissue ratios of 3 and 5 for muscle and skin, respectively. Photodynamic therapy (PDT) performed under these conditions, with 90 mW cm^?2 diode laser irradiation at λ 750 nm for 20 min (total light dose of 108 J cm^?2), resulted in tumor regression. Tumor recurrence was observed only approximately two months after treatment, confirming the efficacy of this PDT against melanoma.     

Design,Synthesis, and Preliminary Biological Evaluation of Pyrrolo[3,4‐c]quinolin‐1‐one and Oxoisoindoline Derivatives as Aggrecanase Inhibitors

A small set of aggrecanase inhibitors based on the pyrrolo[3,4‐c]quinolin‐1‐one or oxoisoindoline frameworks bearing a 4‐(benzyloxy)phenyl substituent and different zinc binding groups were rationally designed and evaluated in silico by docking studies using the crystal structure of the ADAMTS‐5 catalytic domain (PDB code: 3B8Z). The designed compounds were synthesized via straightforward routes and tested for their potential inhibitory activity against ADAMTS‐5 and ADAMTS‐4. Among the compounds containing the pyrrolo[3,4‐c]quinolinone tricyclic system, hydroxamate derivative 2 b inhibited both ADAMTS‐5 and ADAMTS‐4, with IC₅₀ values in the submicromolar range and an inhibitory profile very similar to that of reference carboxylate derivative 11 . Conversely, the corresponding carboxylate derivative 2 a was significantly less active and unable to discriminate between ADAMTS‐5 and ‐4. The structure–activity relationship analysis of pyrroloquinolinone derivatives 2 a – i suggests that the carboxylate or hydroxamate groups of compounds 2 a , b play a key role in the interaction of these compounds with ADAMTS‐5 and ‐4. On the other hand, the oxoisoindoline derivatives 3 a , b lack significant ADAMTS‐4 inhibitory activity and inhibit ADAMTS‐5 showing IC₂₅ values in the micromolar range.     

A Conformational Mimetic Approach for the Synthesis of Carbocyclic Nucleosides as Anti‐HCV Leads

Computer‐aided approaches coupled with medicinal chemistry were used to explore novel carbocyclic nucleosides as potential anti‐hepatitis C virus (HCV) agents. Conformational analyses were carried out on 6‐amino‐1H‐pyrazolo[3,4‐d]pyrimidine (6‐APP)‐based carbocyclic nucleoside analogues, which were considered as nucleoside mimetics to act as HCV RNA‐dependent RNA polymerase (RdRp) inhibitors. Structural insight gained from the modeling studies revealed the molecular basis behind these nucleoside mimetics. The rationally chosen 6‐APP analogues were prepared and evaluated for anti‐HCV activity. RdRp SiteMap analysis revealed the presence of a hydrophobic cavity near C7 of the nucleosides; introduction of bulkier substituents at this position enhanced their activity. Herein we report the identification of an iodinated compound with an EC₅₀ value of 6.6 μM as a preliminary anti‐HCV lead.     

Optimization of the Antiviral Potency and Lipophilicity of Halogenated 2,6‐Diarylpyridinamines as a Novel Class of HIV‐1 NNRTIS

Nineteen new halogenated diarylpyridinamine (DAPA) analogues modified at the phenoxy C‐ring were synthesized and evaluated for anti‐HIV activity and certain drug‐like properties. Ten compounds showed high anti‐HIV activity (EC₅₀<10 nM ). In particular, (E)‐6‐(2′′‐bromo‐4′′‐cyanovinyl‐6′′‐methoxy)phenoxy‐N²‐(4′‐cyanophenyl)pyridin‐2,3‐diamine ( 8 c ) displayed low‐nanomolar antiviral potency (3–7 nM ) against wild‐type and drug‐resistant viral strains bearing the E138K or K101E mutations, which are associated with resistance to rilvipirine ( 1 b ). Compound 8 c exhibited much lower resistance fold changes (RFC: 1.1–2.1) than 1 b (RFC: 11.8–13.0). Compound 8 c also exhibited better metabolic stability (in vitro half‐life) than 1 b in human liver microsomes, possessed low lipophilicity (clog D: 3.29; measured log P: 3.31), and had desirable lipophilic efficiency indices (LE>0.3, LLE>5, LELP<10). With balanced potency and drug‐like properties, 8 c merits further development as an anti‐HIV drug candidate.     

Structure and antimicrobial activity relationship of quaternary N‐alkyl chitosan derivatives against some plant pathogens

In the present work, quaternary chitosans as water‐soluble compounds were prepared based on three‐step process. Schiff bases were firstly synthesized by the reaction between the amino groups of chitosan with aliphatic aldehydes followed by a reduction with sodium borohydride (NaBH₄) to form N‐(alkyl) chitosans. N,N,N‐(dimethyl alkyl) chitosans were then obtained by a reaction of chitosan containing N‐butyl, N‐pentyl, N‐hexyl, N‐heptyl, and N‐octyl substituents with methyl iodide. The compounds were characterized using IR and NMR spectroscopy. Subsequent experiments were conducted to test their antimicrobial activities against the most economic plant pathogenic bacteria of crown gall disease Agrobacterium tumefaciens, soft mold disease Erwinia carotovora, fungi of grey mold Botrytis cinerea, root rot disease Fusarium oxysporum, and damping off disease Pythium debaryanum. Quaternary chitosans enhanced the antibacterial activity and N,N,N‐(dimethyl pentyl) chitosan was the most active one with Minimum Inhibitory Concentration (MIC) of 750 and 1225 mg/L against A. tumefaciens and E. carotovora, respectively. All quaternized chitosans gave stronger antifungal activities than chitosan where N,N,N‐(dimethyl pentyl) chitosan and N,N,N‐(dimethyl octyl) chitosan were significantly the highest in mycelial growth inhibiation against B. cinerea (EC₅₀ = 908 and 383 mg/L, respectively), F. oxysporum (EC₅₀ = 871 and 812 mg/L, respectively), and P. debaryanum (EC₅₀ = 624 and 440 mg/L, respectively). In addition, spore germination of B. cinerea and F. oxysporum was significantly affected with the compounds at the tested concentrations and the inhibition activity was increased with an increase in the chain length of the alkyl substituent. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

Novel Hinge‐Binding Motifs for Janus Kinase 3 Inhibitors: A Comprehensive Structure–Activity Relationship Study on Tofacitinib Bioisosteres

The Janus kinases (JAKs) are a family of cytosolic tyrosine kinases crucially involved in cytokine signaling. JAKs have been demonstrated to be valid targets in the treatment of inflammatory and myeloproliferative disorders, and two inhibitors, tofacitinib and ruxolitinib, recently received their marketing authorization. Despite this success, selectivity within the JAK family remains a major issue. Both approved compounds share a common 7H‐pyrrolo[2,3‐d]pyrimidine hinge binding motif, and little is known about modifications tolerated at this heterocyclic core. In the current study, a library of tofacitinib bioisosteres was prepared and tested against JAK3. The compounds possessed the tofacitinib piperidinyl side chain, whereas the hinge binding motif was replaced by a variety of heterocycles mimicking its pharmacophore. In view of the promising expectations obtained from molecular modeling, most of the compounds proved to be poorly active. However, strategies for restoring activity within this series of novel chemotypes were discovered and crucial structure–activity relationships were deduced. The compounds presented may serve as starting point for developing novel JAK inhibitors and as a valuable training set for in silico models.     

1-Cyclohexyl-4-(4-arylcyclohexyl)piperazines: Mixed σ and human Δ(8)-Δ(7) sterol isomerase ligands with antiproliferative and P-glycoprotein inhibitory activity

Many new chemotherapeutic agents are under preclinical investigation and, despite efforts to more selectively target cancer cells, limitations such as toxicity and inherent resistance are often encountered. Therefore, alternative strategies are needed to treat cancer and overcome such limitations. We describe novel cyclohexylpiperazine derivatives, designed as mixed affinity ligands for sigma (σ) receptors and human Δ₈–Δ₇ sterol isomerase (HSI) ligands, which also exhibit P‐glycoprotein (P‐gp) inhibitory activity, with the aim of exploiting the antiproliferative effects mediated by σ and HSI sites while overcoming P‐gp‐mediated resistance. All of the compounds displayed high affinities for σ receptors and HSI sites, P‐gp inhibitory activity, and σ₂ receptor agonist antiproliferative activity. Antiproliferative activity was also tested in PC‐3 cells to establish σ₁ and HSI contribution. Compound cis‐ 11 , which displayed the best antiproliferative and P‐gp inhibitory activities, was co‐administered with 0.1 μM doxorubicin in MDCK‐MDR1 cells. Compound cis‐ 11 caused 70 % and 90 % cell death when co‐administered at 30 μM and 50 μm, respectively. When administered alone, cis‐ 11 resulted in 50 % cell death, demonstrating its single agent antitumor properties in a tumor cell line overexpressing P‐gp.     

Synthesis,Cytotoxicity, and Insight into the Mode of Action of Re(CO)3 Thymidine Complexes

Nucleoside analogues are extensively used in the treatment of cancer and viral diseases. The antiproliferative properties of organorhenium(I) complexes, however, have been scarcely explored to date. Herein we present the syntheses, characterization, and in vitro evaluation of Re^I(CO)₃ core complexes of thymidine and uridine. For the binding of the Re^I(CO)₃ core, a tridentate dipicolylamine metal chelate was introduced at positions C5′, C2′, N3, and C5 with spacers of various lengths. The corresponding organometallic thymidine complexes were fully characterized by IR and NMR spectroscopy and mass spectrometry. Their cytotoxicity was assessed against the A549 lung carcinoma cell line. Toxicity is dependent on the site and mode of conjugation as well as on the nature and the length of the tether. Moderate toxicity was observed for conjugates carrying the rhenium moiety at position C5′ or N3 (IC₅₀=124–160 μM ). No toxicity was observed for complexes modified at C2′ or C5. Complex 53 , with a dodecylene spacer at C5′, exhibits remarkable toxicity and is more potent than cisplatin, with an IC₅₀ value of 6.0 μM . To the best of our knowledge, this is the first report of the antiproliferative properties of [M(CO)₃]⁺¹–nucleoside conjugates. In competitive inhibition experiments with A549 cell lysates and purified recombinant human thymidine kinase 1 (hTK‐1), enzyme inhibition was observed for complexes modified at either N3 or C5′, but our results suggest that the toxicity cannot be attributed solely to interaction with hTK‐1.     

Bis(dipyridophenazine)(2‐(2′‐pyridyl)pyrimidine‐4‐carboxylic acid)ruthenium(II) Hexafluorophosphate: A Lesson in Stubbornness

Ruthenium complexes are currently considered to be among the most promising alternatives to platinum anticancer drugs. In this work, thirteen structural analogues and organelle/receptor‐targeting peptide bioconjugates of a cytotoxic bis(dppz)‐Ru^II complex [Ru(dppz)₂(CppH)](PF₆)₂ ( 1 ) were prepared, characterized, and assessed for their cytotoxicity and cellular localization (CppH=2‐(2′‐pyridyl)pyrimidine‐4‐carboxylic acid; dppz=dipyrido[3,2‐a:2′,3′‐c]phenazine). It was observed that structural modifications (lipophilicity, charge, and size‐based) result in the cytotoxic potency of 1 being compromised. Confocal microscopy studies revealed that unlike 1 , the screened complexes/bioconjugates do not have a preferential accumulation in mitochondria. The results of this important structure–activity relationship strongly support our initial hypothesis that accumulation in mitochondria is crucial for 1 to exert its cytotoxic action.     

Discovery and development of thiazolo[3,2-a]pyrimidinone derivatives as general inhibitors of Bcl-2 family proteins

A class of compounds with a common thiazolo[3,2‐a]pyrimidinone motif has been developed as general inhibitors of Bcl‐2 family proteins. The lead compound was originally identified in a random screening of a small compound library using a fluorescence polarization‐based competitive binding assay. Its binding to the Bcl‐x_L protein was further confirmed by ¹⁵N‐HSQC NMR experiments. Structural modifications on the lead compound were guided by the outcomes of molecular modeling studies. Among the 42 compounds obtained, a number of them exhibited much improved binding affinities to Bcl‐2 family proteins as compared to the lead compound. The most potent compound, BCL‐LZH‐ 40 , inhibited the binding of BH3 peptides to Bcl‐x_L, Bcl‐2, and Mcl‐1 with inhibition constants (K_i) of 17, 534, and 200 nM , respectively.