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1.
A new class of nonpeptidic inhibitors of the malarial aspartic protease plasmepsin II (PMII) with up to single‐digit micromolar activities (IC50 values) was developed by structure‐based de novo design. The active‐site matrix used in the design was based on an X‐ray crystal structure of PMII, onto which the major conformational changes seen in the structure of renin upon complexation of 4‐arylpiperidines – including the unlocking of a new hydrophobic (flap) pocket – were modeled. The sequence identity of 35% between mature renin and PMII had prompted us to hypothesize that an induced‐fit adaptation around the active site as observed in renin might also be effective in PMII. The new inhibitors contain a central 11‐azatricyclo[6.2.1.02,7]undeca‐2(7),3,5‐triene core, which, in protonated form, undergoes ionic H‐bonding with the two catalytic Asp residues at the active site of PMII (Figs. 1 and 2). This tricyclic scaffold is readily prepared by a Diels? Alder reaction between an activated pyrrole and a benzyne species generated in situ (Scheme 1). Two substituents with naphthyl or 1,3‐benzothiazole moieties are attached to the central core (Schemes 14) for accommodation in the hydrophobic flap and S1/S3 (or S2′, depending on the optical antipode of the inhibitor) pockets at the active site of the enzyme. The most‐potent inhibitors (±)‐ 19a – 19c (IC50 3–5 μM ) and (±)‐ 23b (2 μM ) (Table) bear an additional Cl‐atom on the 1,3‐benzothiazole moiety to fully fill the rear of the flap pocket. Optimization of the linker between the tricyclic scaffold and the 1,3‐benzothiazole moiety, based on detailed conformational analysis (Figs. 3 and 4), led to a further small increase in inhibitory strength. The new compounds were also tested against other aspartic proteases. They were found to be quite selective against renin, while the selectivity against cathepsin D and E, two other human aspartic proteases, is rather poor (Table). The detailed SARs established in this investigation provide a valuable basis for the design of the next generations of more‐potent and ‐selective PMII inhibitors with potential application in a new antimalarial therapy.  相似文献   

2.
The increasing prevalence of multidrug‐resistant strains of the malarial parasite Plasmodium falciparum requires the urgent development of new therapeutic agents with novel modes of action. The vacuolar malarial aspartic proteases plasmepsin (PM) I, II, and IV are involved in hemoglobin degradation and play a central role in the growth and maturation of the parasite in the human host. We report the structure‐based design, synthesis, and in vitro evaluation of a new generation of PM inhibitors featuring a highly decorated 7‐azabicyclo[2.2.1]heptane core. While this protonated central core addresses the catalytic Asp dyad, three substituents bind to the flap, the S1/S3, and the S1′ pockets of the enzymes. A hydroformylation reaction is the key synthetic step for the introduction of the new vector reaching into the S1′ pocket. The configuration of the racemic ligands was confirmed by extensive NMR and X‐ray crystallographic analysis. In vitro biological assays revealed high potency of the new inhibitors against the three plasmepsins (IC50 values down to 6 nM ) and good selectivity towards the closely related human cathepsins D and E. The occupancy of the S1′ pocket makes an essential contribution to the gain in binding affinity and selectivity, which is particularly large in the case of the PM IV enzyme. Designing non‐peptidic ligands for PM II is a valid route to generate compounds that inhibit the entire family of vacuolar plasmepsins.  相似文献   

3.
Structure‐activity relationships for new members of a class of nonpeptidic, low‐molecular‐weight inhibitors of thrombin, a key serine protease in the blood coagulation cascade, are described. These compounds, which originate from X‐ray‐structure‐based design, feature a conformationally rigid, bi‐ or tricyclic core from which side chains diverge into the four major binding pockets (distal D, proximal P, recognition or specificity S1, and oxyanion hole O) at the thrombin active site (Fig. 1). Phenylamidinium is the side chain of choice for the S1 pocket, while the most active inhibitors orient an i‐Pr group into the P‐pocket (Table 1). The key step in the synthesis of the inhibitors is the construction of the central bi‐ or tricyclic scaffold by 1,3‐dipolar cycloaddition of an in situ prepared azomethine ylide and an N‐substituted maleimide (Schemes 1–3, and 8–10). One series of compounds was designed to explore the binding features of the large hydrophobic D pocket. This pocket provides space for lipophilic residues as bulky as benzhydryl groups. A new strategy was developed, allowing introduction of these sterically demanding substituents very late in the synthesis (Schemes 5 and 6). Benzhydryl derivative (±)‐ 2 was found to be the most selective member (Ki (trypsin)/Ki (thrombin)=1200) of this class of nonpeptidic thrombin inhibitors, while the ‘dipiperonyl' analog (±)‐ 3 (Ki=9 nM , 7.60‐fold selectivity) displays the highest potency of all compounds prepared so far (Table 1). A second series of inhibitors features side chains designed to orient into the oxyanion hole and to undergo H‐bonding with the backbone NH groups lining the catalytic site of the enzyme. Unfortunately, neither activity nor selectivity could be substantially improved by introduction of these substituents (Table 2). Presumably, the high degree of pre‐organization and the rigidity of the tightly bound scaffolds prevents the new substituents from assuming a position that would allow favorable interactions in the oxyanion hole. However, the oxyanion hole and the S1′ pocket next to it were found to be capable of accommodating quite large groups, which leaves much room for further exploration.  相似文献   

4.
A new class of nonpeptidic inhibitors of the ZnII‐dependent metalloprotease neprilysin with IC50 values in the nanomolar activity range (0.034–0.30 μM ) were developed based on structure‐based de novo design (Figs. 1 and 2). The inhibitors feature benzimidazole and imidazo[4,5‐c]pyridine moieties as central scaffolds to undergo H‐bonding to Asn542 and Arg717 and to engage in favorable ππ stacking interactions with the imidazole ring of His711. The platform is decorated with a thiol vector to coordinate to the ZnII ion and an aryl residue to occupy the hydrophobic S1′ pocket, but lack a substituent for binding in the S2′ pocket, which remains closed by the side chains of Phe106 and Arg110 when not occupied. The enantioselective syntheses of the active compounds (+)‐ 1 , (+)‐ 2 , (+)‐ 25 , and (+)‐ 26 were accomplished using Evans auxiliaries (Schemes 2, 4, and 5). The inhibitors (+)‐ 2 and (+)‐ 26 with an imidazo[4,5‐c]pyridine core are ca. 8 times more active than those with a benzimidazole core ((+)‐ 1 and (+)‐ 25 ) (Table 1). The predicted binding mode was established by X‐ray analysis of the complex of neprilysin with (+)‐ 2 at 2.25‐Å resolution (Fig. 4 and Table 2). The ligand coordinates with its sulfanyl residue to the ZnII ion, and the benzyl residue occupies the S1′ pocket. The 1H‐imidazole moiety of the central scaffold forms the required H‐bonds to the side chains of Asn542 and Arg717. The heterobicyclic platform additionally undergoes π‐π stacking with the side chain of His711 as well as edge‐to‐face‐type interactions with the side chain of Trp693. According to the X‐ray analysis, the substantial advantage in biological activity of the imidazo‐pyridine inhibitors over the benzimidazole ligands arises from favorable interactions of the pyridine N‐atom in the former with the side chain of Arg102. Unexpectedly, replacement of the phenyl group pointing into the deep S1′ pocket by a biphenyl group does not enhance the binding affinity for this class of inhibitors.  相似文献   

5.
A novel class of nonpeptidic, active, and selective thrombin inhibitors has resulted from X‐ray‐structure‐based design and subsequent improvement of the initial lead molecules. These inhibitors possess a bi‐ or tricyclic central core structure with attached side chains to reach the three binding pockets (selectivity S1 pocket, distal D pocket, and proximal P pocket) present in the active site of the enzyme. The key step in the preparation of these compounds is the 1,3‐dipolar cycloaddition between an azomethine ylide, prepared in situ by the decarboxylative method from an aromatic aldehyde and an α‐amino acid, with an N‐substituted maleimide (e.g., see Schemes 1 and 2). All potent inhibitors contain an amidinium residue in the side chain for incorporation into the S1 pocket, which was introduced in the last step of the synthesis by a Pinner reaction. The compounds were tested in biological assays for activity against thrombin and the related serine protease trypsin. The first‐generation lead compounds (±)‐ 11 and (±)‐ 19 (Scheme 1) with a bicyclic central scaffold showed Ki values for thrombin inhibition of 18 μM and 0.67 μM , respectively. Conformationally more restricted second‐generation analogs (Scheme 2) were more active ((±)‐ 22i : Ki=90 nM (Table 1)); yet the selectivity for thrombin over trypsin remained weak. In the third‐generation compounds, a small lipophilic side chain for incorporation into the hydrophobic P pocket was introduced (Schemes 7 and 8). Since this pocket is present in thrombin but not in trypsin, an increase in binding affinity was accompanied by an increase in selectivity for thrombin over trypsin. The most selective inhibitor (Ki=13 nM , 760‐fold selectivity for thrombin over trypsin; Table 2) was (±)‐ 1 with an i‐Pr group for incorporation into the P pocket. Optical resolution of (±)‐ 1 (Scheme 9) provided (+)‐ 1 with a Ki value of 7 nM and a 740‐fold selectivity, whereas (−)‐ 1 was 800‐fold less active (Ki=5.6 μM , 21‐fold selectivity). The absolute configuration of the stronger‐binding enantiomer was assigned based on the X‐ray crystal structure of the complex formed between thrombin and this inhibitor. Compound (+)‐ 1 mimics the natural thrombin substrate, fibrinogen, which binds to the enzyme with the Ph group of a phenylalanine (piperonyl in (+)‐ 1 ) in the distal D pocket, with the i‐Pr group of a valine (i‐Pr in (+)‐ 1 ) in the proximal P pocket, and with a guanidinium side chain of an arginine residue (phenylamidinium group in (+)‐ 1 ) in the selectivity S1 pocket of thrombin. A series of analogs of (±)‐ 1 with the phenylamidinium group replaced by aromatic and aliphatic rings bearing OH or NH2 groups (Schemes 10 – 14) were not effectively bound by thrombin. A number of X‐ray crystal‐structure analyses of free inhibitors confirmed the high degree of preorganization of these compounds in the unbound state. Since all inhibitors prefer similar modes of association with thrombin, detailed information on the strength of individual intermolecular bonding interactions and their incremental contribution to the overall free energy of complexation was generated in correlative binding and X‐ray studies. The present study demonstrates that defined mutations in highly preorganized inhibitors provide an attractive alternative to site‐directed mutagenesis in exploring molecular‐recognition phenomena at enzyme active sites.  相似文献   

6.
Neprilysin (NEP; neutral endopeptidase EC 3.4.24.11) is a ZnII‐dependent, membrane‐bound endopeptidase. NEP is widely distributed in the organs, particularly in the kidneys and lungs, and it is involved in the metabolism of a number of smaller regulatory peptides. Inhibition of NEP has been proposed as a potential target for analgesic and antihypertensive therapies. In this study, new nonpeptidic inhibitors of neprilysin ((±)‐ 1 , (±)‐ 43 , (±)‐ 45 , and (±)‐ 46 ; Table) were designed, based on the X‐ray crystal structure of NEP complexed to phosphoramidon (Fig. 1). They feature an imidazole ring as the central scaffold, acting as a peptide bond isoster to undergo H‐bonding with the side chains of Asn542 and Arg717 (Fig. 2). The scaffold is decorated with a thiol group to ligate to the ZnII ion and two aromatic residues to bind into the hydrophobic S1′ and S2′ pockets. The synthesis of the new inhibitors was approached by two routes (Schemes 1–4 and 5–8), with the second one involving a double directed ortho‐metallation of the imidazole platform and a Stille cross‐coupling, providing the desired target molecules as hydrochloride salts. In a fluorescence assay, inhibitors (±)‐ 1 , (±)‐ 43 , (±)‐ 45 , and (±)‐ 46 all exhibit IC50 values in the single‐digit micromolar activity range (2–4 μM , Table), which validates the binding mode postulated by modeling. Useful guidelines for a next lead optimization cycle were obtained in several control runs.  相似文献   

7.
This paper describes the rational design, synthesis, and biological evaluation of a new generation of inhibitors of the bacterial enzyme tRNA‐guanine transglycosylase (TGT), which has been identified as a new target in the fight against bacillary dysentery (Shigellosis). The enzyme catalyzes the exchange of guanine in the anticodon wobble position of tRNA by the modified base preQ1, a guanine derivative, according to a ping‐pong mechanism involving a covalent TGT‐tRNA intermediate (Fig. 2). Based on computer modeling (Fig. 3), lin‐benzoguanine (6‐aminoimidazol[4,5‐g]quinazolin‐8(7H)‐one ( 2 )) was selected as an extended central scaffold, to form up to seven in‐plane intermolecular H‐bonds with the protein while sandwiching between Tyr106 and Met260. Versatile synthetic protocols were developed for the synthesis of 2 , and derivatives with phenyl, benzyl, and 2‐phenylethyl side chains (i.e., 16, 17a , and 12a, 12b, 13, 17 , resp.) to reach into the lipophilic pocket lined by Val282, Val45, and Leu68 (Schemes 1–3). To account for the limited solubility of the new ligands and in consequence of a recently developed detailed understanding of the mechanism of TGT catalysis (Fig. 2), the enzyme kinetic assay was completely redesigned, providing competitive (Kic) and uncompetitive (Kiu) inhibition constants with respect to tRNA binding by TGT. The modifications of the various parameters in the new assay are described in detail. Binding affinities of the new inhibitors were found to be in the single‐digit micromolar range (Kic values, Fig. 8). Decoration of the lin‐benzoguanine scaffold with lipophilic residues only gave a modest improvement in biological activity which was explained on structural grounds with the help of four crystal structures (Fig. 10) obtained by soaking the protein with inhibitors 2 and 12a – 12c . Both biochemical and biostructural analyses reported in this paper provide a fertile basis for the development of more potent future generations of TGT inhibitors.  相似文献   

8.
The bromination (CuBr2, AcOEt/CHCI3) plus Favorskii rearrangement (EtONa, EtOH) of N‐carbethoxytropinone ( 4 ), readily available from tropinone ( 3 ), affords mixtures of exo‐ and endo‐isomers of 2,7‐dicarbethoxy‐7‐azabicyclo[2.2.1]heptane ( 1b ) in variable and moderate chemical yield (maximum 37%). The bromination (Br2, HBr/AcOH) reaction of compound 4 gives ethyl trans‐2,4‐dibromo‐3‐oxo‐8‐azabicyclo[3.2.1]octane‐8‐carboxylate ( 5 ) in 99% yield, a product that on Favorskii rearrangement (EtONa/EtOH) affords ethyl 2,2‐diethoxy‐3‐oxo‐8‐azabicyclo[3.2.1]octane‐8‐carboxylate in moderate yield ( 6 ) (52%).  相似文献   

9.
BACKGROUND: The aspartic proteinase renin plays an important physiological role in the regulation of blood pressure. It catalyses the first step in the conversion of angiotensinogen to the hormone angiotensin II. In the past, potent peptide inhibitors of renin have been developed, but none of these compounds has made it to the end of clinical trials. Our primary aim was to develop novel nonpeptide inhibitors. Based on the available structural information concerning renin-substrate interactions, we synthesized inhibitors in which the peptide portion was replaced by lipophilic moieties that interact with the large hydrophobic S1/S3-binding pocket in renin. RESULTS: Crystal structure analysis of renin-inhibitor complexes combined with computational methods were employed in the medicinal-chemistry optimisation process. Structure analysis revealed that the newly designed inhibitors bind as predicted to the S1/S3 pocket. In addition, however, these compounds interact with a hitherto unrecognised large, distinct, sub-pocket of the enzyme that extends from the S3-binding site towards the hydrophobic core of the enzyme. Binding to this S3(sp) sub-pocket was essential for high binding affinity. This unprecedented binding mode guided the drug-design process in which the mostly hydrophobic interactions within subsite S3(sp) were optimised. CONCLUSIONS: Our design approach led to compounds with high in vitro affinity and specificity for renin, favourable bioavailability and excellent oral efficacy in lowering blood pressure in primates. These renin inhibitors are therefore potential therapeutic agents for the treatment of hypertension and related cardiovascular diseases.  相似文献   

10.
11.
Skyllamycin is a non‐ribosomally synthesized cyclic depsipeptide from Streptomyces sp. Acta 2897 that inhibits PDGF‐signaling. The peptide scaffold contains an N‐terminal cinnamoyl moiety, a β‐methylation of aspartic acid, three β‐hydroxylated amino acids and one rarely occurring α‐hydroxy glycine. With the exception of α‐hydroxy glycine, the stereochemistry of the amino acids was assigned by comparison to synthetic reference amino acids applying chiral GC‐MS and Marfey‐HPLC analysis. The stereochemistry of α‐hydroxy glycine, which is unstable under basic and acidic conditions, was determined by conformational analysis, employing a combination of data from NOESY‐NMR spectroscopy, simulated annealing and free MD simulations. The simulation procedures were applied for both R‐ and S‐configured α‐hydroxy glycine of the skyllamycin structure and compared to the NOESY data. Both methods, simulated annealing and free MD simulations independently support S‐configured α‐hydroxy glycine thus enabling the assignment of all stereocenters in the structure of skyllamycin and devising the role of two‐component flavin dependent monooxygenase (Sky39) as S‐selective.  相似文献   

12.
We have developed a short and highly efficient synthetic strategy towards the hitherto hardly known 3,5- and 3,6-disubstituted 2,3,4,7-tetrahydro-1H-azepine scaffold via a ring-closing metathesis approach utilizing inexpensive and readily available starting material such as methyl acrylate and allylamine. Both seven-membered azacycle scaffolds bearing suitable functional groups, which can easily be modified by means of standard synthetic chemistry, serve as non-peptidic heterocyclic core structures for the further design and synthesis of aspartic protease inhibitors. Through specific decoration with appropriate side chains, individual inhibitors can be tailored with respect to selectivity towards particular family members. A first generation of this class of non-peptidic inhibitors have been tested against the aspartic proteases Plasmepsin II and HIV-I protease, respectively, showing promising activity as well as selectivity with IC50 values in the micromolar range.  相似文献   

13.
γ‐Secretase, a multiprotein aspartic protease crucial to Alzheimer's dementia, is not available for NMR experiments and has, so far, escaped crystallization. A positional scan of the aspartic protease by reactive probes may provide the necessary structural information for drug development. We describe here the synthesis of acid‐labile compounds based on the known inhibitor DAPT ( 1 ), e.g., the N‐terminally functionalized diazo compound 4 or the C‐terminally acid‐labile (cyclopropylmethyl)ester 11 , which were designed to react in the specific acidic active‐site environment of the aspartic protease presenilin 1. The acid‐labile DAPT analogues 11 – 13 , indeed, displayed strong inhibition in a cell‐free γ‐secretase assay.  相似文献   

14.
Herein, we describe the use of thioglycosides as glycosidase inhibitors by employing novel modifications at the reducing end of these glycomimetics. The inhibitors display a basic galactopyranosyl unit (1→4)‐bonded to a 3‐deoxy‐4‐thiopentopyranose moiety. The molecular basis of the observed inhibition has been studied by using a combination of NMR spectroscopy and molecular modeling techniques. It is demonstrated that these molecules are not recognized by Escherichia coli β‐galactosidase in their ground‐state conformation, with a conformational selection process taking place. In fact, the observed conformational distortion depends on the chemical nature of the compounds and results from the rotation around the glycosidic linkage (variation of Φ or Ψ) or from the deformation of the six‐membered ring of the pentopyranose. The bound conformations of the ligand are adapted in the enzymatic pocket with a variety of hydrogen‐bond, van der Waals, and stacking interactions.  相似文献   

15.
Successful lead optimization in structure‐based drug discovery depends on the correct deduction and interpretation of the underlying structure–activity relationships (SAR) to facilitate efficient decision‐making on the next candidates to be synthesized. Consequently, the question arises, how frequently a binding mode (re)‐validation is required, to ensure not to be misled by invalid assumptions on the binding geometry. We present an example in which minor chemical modifications within one inhibitor series lead to surprisingly different binding modes. X‐ray structure determination of eight inhibitors derived from one core scaffold resulted in four different binding modes in the aspartic protease endothiapepsin, a well‐established surrogate for e.g. renin and β‐secretase. In addition, we suggest an empirical metrics that might serve as an indicator during lead optimization to qualify compounds as candidates for structural revalidation.  相似文献   

16.
The cyclic 16‐membered pentadepsipeptide cyclo(Tro‐Aib‐Aib‐Aib‐Aib) ( 1 ) was crystallized from MeOH/AcOEt/CH2Cl2, and its structure was established by X‐ray crystallography (Fig. 1). There are two symmetry‐independent molecules with different conformations in the asymmetric unit. Two intramolecular H‐bonds stabilize two β‐turns in each molecule. On the other hand, two of the four Aib residues are forced to assume a nonfavorable nonhelical conformation in each of the symmetry‐independent molecules (Table 1). The conformational study in CDCl3 solution by NMR spectroscopy and molecular dynamics (MD) simulations indicate that the averaged structure (Fig. 3) is almost the same as in the solid state.  相似文献   

17.
A combinatorial library of norstatine-type peptide isosters as putative inhibitors of aspartic proteases is presented. The library was synthesized using a split-and-mix strategy designed to afford a one-bead-two-compounds library with the isosteric elements positioned centrally in peptide chains. Application of ladder synthesis during library generation enabled structure identification by MALDI-TOF mass spectroscopy. The library was screened against aspartic protease renin, and two types of inhibitors were identified, that is, XXX-psi[CHRCHOH)-XXX and an aldehyde arising from unreacted starting material. Selected hits were resynthesized and assayed in solution, revealing inhibitors of nanomolar potency.  相似文献   

18.
A new route via intermediate pseudoenantiomers was developed to synthesize racemic and enantiomerically pure new non‐peptidic inhibitors of thrombin, a key serine protease in the blood‐coagulation cascade. These ligands feature a conformationally rigid tricyclic core and are decorated with substituents to fill the major binding pockets (distal (D), proximal (P), selectivity (S1), and oxyanion hole) at the thrombin active site (Fig. 1). The key step in the preparation of the new inhibitors is the 1,3‐dipolar cycloaddition between an optically active azomethine ylide, prepared in situ from L ‐(4R)‐hydroxyproline and 4‐bromobenzaldehyde, and N‐piperonylmaleimide (Scheme 1). According to this protocol, tricyclic imide (compounds (±)‐ 15 ‐(±)‐ 18 and (+)‐ 21 ) and lactam (compound (+)‐ 2 ) inhibitors with OH or ether substituents at C(7) in the proline‐derived pyrrolidine ring were synthesized to specifically explore the binding features of the oxyanion hole (Schemes 2–4). Biological assays (Table) showed that the polar oxyanion hole in thrombin is not suitable for the accommodation of bulky substituents of low polarity, thereby confirming previous findings. In contrast, tricyclic lactam (+)‐ 2 (Ki=9 nM , Ki(trypsin)/Ki(thrombin)=1055) and tricyclic imide (+)‐ 21 (Ki=36 nM , Ki(trypsin)/Ki(thrombin)=50) with OH‐substituents at the (R)‐configured C(7)‐atom are among the most‐potent and most‐selective thrombin inhibitors in their respective classes, prepared today. While initial modeling predicted H‐bonding between the OH group at C(7) in (+)‐ 2 and (+)‐ 21 with the H2O molecule bound in the oxyanion hole (Fig. 2), the X‐ray crystal structure of the complex of (+)‐ 21 (Fig. 7, b) revealed a different interaction for this group. The propionate side chain of Glu192 undergoes a conformational change, thereby re‐orienting towards the OH group at C(7) under formation of a very short ionic H‐bond (O? H????OOC; d(O???O)=2.4 Å). The energetic contribution of this H‐bond, however, is negligible, due to its location on the surface of the protein and the unfavorable conformation of the H‐bonded propionate side chain.  相似文献   

19.
An efficient synthetic route based on generation and subsequent electrophilic reaction of a Boc-protected azabicyclo[2.2.1]heptane anion to prepare a potent GlyT1 uptake inhibitor (1) is described.  相似文献   

20.
Functionalized oligomeric organic compounds with well‐defined β‐proline scaffold have been synthesized by a cycloadditive oligomerization approach in racemic and enantiopure forms. The structure of the novel β‐peptides was investigated by NMR spectroscopic and X‐ray methods determining the conformational shapes of the β‐proline oligomers in solution and solid states. The main structural elements subject to conformational switches are β‐peptide bonds between 5‐arylpyrrolidine‐2‐carboxylic acid units existing in Z/E configurations. The whole library of short β‐peptides and intermediate acrylamides has been tested on antiproliferative activity towards the hormone‐refractory prostate cancer cell line PC‐3 revealing several oligomeric compounds with low micromolar and submicromolar activities. Bromine‐substituted dimeric and trimeric acrylamides induced caspase‐dependent apoptosis of PC‐3 cells through cell‐cycle arrest and mitochondrial damage.  相似文献   

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