Synthesis,Cytotoxic Evaluation,and In Silico Studies of 4‐Substituted Coumarins

Two series of coumarins possessing the aniline‐ and heterocyclic ring at 4^th position have been synthesized and evaluated for their in vitro cytotoxic activity against MCF‐7 cancer cell line in MTT assay. Structure activity relationship (SAR) studies reveal that the electron donor group at position‐8 of coumarin played an important role in cytotoxic activity. Compound VIId showed the potent cytotoxic activity followed by compound Xa with IC₅₀ = 6.25 and 6.50 μM, respectively. A docking study has also been carried out for the most potent compound to get an insight into molecular interactions with p50 subunit of NF‐κB protein.     

Novel 5‐Methyl‐2‐[(un)substituted phenyl]‐4‐{4,5‐dihydro‐ 3‐[(un)substituted phenyl]‐5‐(1,2,3,4‐tetrahydroisoquinoline‐2‐yl)pyrazol‐1‐yl}‐oxazole Derivatives: Synthesis and Anticancer Activity

Eleven novel 5‐methyl‐2‐[(un)substituted phenyl]‐4‐{4,5‐dihydro‐3‐[(un)substituted phenyl]‐5‐(1,2,3,4‐tetrahydroisoquinoline‐2‐yl)pyrazol‐1‐yl}‐oxazole derivatives were synthesized and characterized by elemental analysis, ESI‐MS, ¹H NMR and ¹³C NMR. All of the compounds have been screened for their antiproliferative activities against PC‐3 cell (human prostate cancer) and A431 cell (human epidermoid carcinoma cancer) lines in vitro. The results revealed that compounds 4g , 4j and 4k exhibited the strong inhibitory activities against the PC‐3 cell lines (with IC₅₀ values of 2.8±0.11, 3.1±0.10 and 3.0±0.06 μg/mL, respectively).     

Synthesis,in vitro Antimicrobial,and Cytotoxic Activities of New 1,3,4‐Oxadiazin‐5(6H)‐one Derivatives from Dehydroabietic Acid

A series of new 1,3,4‐oxadiazin‐5(6H)‐one derivatives ( 6a–n ) of dehydroabietic acid were designed and synthesized as potential antimicrobial and antitumor agents. Their structures were characterized by IR, ¹H NMR, ¹³C NMR, MS, and elemental analyses. All the title compounds were evaluated for their antimicrobial activity against four bacterial and three fungal strains using the serial dilution method. Among them, compound 6e showed the highest antibacterial activity against Bacillus subtilis with a minimum inhibitory concentration (MIC) value of 1.9 μg/mL. In addition, the in vitro cytotoxic activities of the title compounds were also assayed against three human carcinoma cell lines (MCF‐7, SMMC‐7721, and HeLa) through the MTT colorimetric method. As a result, compounds 6b , 6g , 6k, and 6m exhibited significant inhibition against at least one cell line with IC₅₀ values below 10 μM. Compound 6m was especially found to be the most potent derivative with IC₅₀ values of 2.26 ± 0.23, 0.97 ± 0.11, and 1.89 ± 0.31 μM against MCF‐7, SMMC‐7721, and HeLa cells, respectively, comparable to positive control etoposide.     

Design,Synthesis, and Evaluation of 3‐((4‐(t‐Butyl)‐2‐(2‐benzylidenehydrazinyl)thiazol‐5‐yl)methyl)quinolin‐2(1H)‐ones as Neuraminidase Inhibitors

A series of novel 3‐((4‐(t‐butyl)‐2‐(2‐benzylidenehydrazinyl)thiazol‐5‐yl)methyl)quinolin‐2(1H)‐ones ( 7a – 7z ) were designed, synthesized and evaluated for their ability of inhibiting neuraminidase (NA) of in?uenza H1N1 virus. Some compounds displayed moderate influenza NA inhibitory activity. Compound 7l with the scaffold of 2‐(2‐(2‐methoxybenzylidene)hydrazinyl)thiazole was the best one, exhibiting moderate NA inhibitory activity with IC₅₀ of 44.66 µmol/L. Structure‐activity relationship showed that compounds with methoxy or hydroxy groups at the ortho position, fluorine and nitro groups at the meta position and chlorine and bromine groups at the para position of phenyl ring were more active. Docking study indicated that compound 7l has important interactions with some key residues (including Asp151, Glu119, Arg292, Tyr406, and Asn347) and binds to 430‐cavity adjacent to NA active site.     

(1S,2S,3R,6R)‐6‐Aminocyclohex‐4‐ene‐1,2,3‐triol (= (−)‐Conduramine B‐1) Is a Selective Inhibitor of α‐Mannosidases. Its Inhibitory Activity Is Enhanced by N‐Benzylation

(−)‐ and (+)‐Conduramine B‐1 ((−)‐ and (+)‐ 5 , resp.) have been derived from (+)‐ and (−)‐7‐oxabicyclo[2.2.1]hept‐5‐en‐2‐one (‘naked sugars’ of the first generation). Although (−)‐ 5 imitates the structure of β‐glucosides, it does not inhibit β‐glucosidases but inhibits α‐mannosidases selectively. N‐Benzylation of (−)‐ 5 improves the potency of conduramine B‐1 as α‐mannosidase inhibitor and also generates compounds inhibiting β‐glucosidases. For instance, (−)‐N‐benzyl‐conduramine B‐1 ((−)‐ 19a ) is a competitive inhibitor of β‐glucosidase from almonds (IC₅₀ = 32 μM , K_i = 10 μM ) and a weak inhibitor of α‐mannosidases from jack bean (IC₅₀ = 171 μM ) and from almonds (IC₅₀ = 225 μM ) whereas (−)‐N‐(4‐phenylbenzyl)conduramine B‐1 ((−)‐ 19g ) is a good inhibitor of α‐mannosidase from jack beans (IC₅₀ = 29 μM , K_i = 4.8 μM ) and a weaker inhibitor of β‐glucosidase from almonds (IC₅₀ = 32 μM , K_i = 7.8 μM ) (Table 1).     

Synthesis of 4‐alkyl‐1,2‐diphenyl‐3,5‐dioxopyrazolidines possessing aryl methylsulfonyl and sulfonamide pharmacophores for evaluation as selective cyclooxygenase‐2 (COX‐2) inhibitors

A group of 1,2‐diphenyl‐3,5‐dioxopyrazolidines possessing a methylsulfonyl ( 11 ) or sulfonamide ( 15 ) substituent at the para position of the N¹‐phenyl ring, in conjunction with a hydrogen, methyl or fluoro sub‐stituent at the para position of the N²‐phenyl ring, and a C‐4 n‐butyl, methyl or spiro‐cyclopropyl substituent were synthesized for evaluation as potential cyclooxygenase‐2 (COX‐2) selective inhibitor antiinflammatory agents. The title compounds 11 and 15 were synthesized using a four‐step and a three‐step reaction sequence, respectively. Thus, the acetic acid promoted condensation of a nitrosobenzene 5 with an aniline derivative ( 6, 12 ) gave the corresponding azobenzene product ( 8, 13 ) which was reduced with zinc dust in the presence of ammonium chloride to yield the corresponding hydrazobenzene ( 9, 14 ). Base‐catalyzed condensation of 9 and 14 with a malonyl dichloride ( 10 ) afforded the target 3,5‐dioxopyrazolidine product ( 11,15 ). 4‐n‐Butyl‐1‐(4‐methylsulfonylphenyl)‐2‐phenyl‐3,5‐dioxopyrazolidine ( 11a ) was a selective COX‐1 inhibitor (COX‐1 IC₅₀ = 8.48 μM). In contrast, 4‐n‐butyl‐1‐(4‐methylsulfonylphenyl)‐2‐(4‐tolyl)‐3,5‐dioxopyrazolidine ( 11b , COX‐2 IC₅₀ = 11.45 μM) and 4‐n‐butyl‐1‐(4‐methylsulfonylphenyl)‐2‐(4‐fluorophenyl)‐3,5‐dioxopyrazoli‐dine ( 11c , COX‐2 IC₅₀ = 9.86 μM) were about 46‐fold and 20‐fold less selective COX‐2 inhibitors respectively, relative to the reference drug celecoxib.     

Peripheral or nonperipheral tetra‐[4‐(9H‐carbazol‐9‐yl)phenoxy] substituted cobalt(II), manganese(III) phthalocyanines: Synthesis,acetylcholinesterase, butyrylcholinesterase,and α‐glucosidase inhibitory effects and anticancer activities

In this work, peripheral or nonperipheral tetra‐[4‐(9H‐carbazol‐9‐yl)phenoxy] substituted cobalt(II), manganese (III) phthalocyanines were synthesized for the first time. Their acetylcholinesterase from Electrophorus electricus (AChE), butyrylcholinesterase equine serum (BuChE), and α‐glucosidase Saccharomyces cerevisiae inhibition were investigated spectrophotometrically. Finally, in vitro cytotoxicities of the compounds were investigated on human neuroblastoma (SH‐SY5Y) cell line using MTT cell viability assay. The compounds inhibited to enzymes in the range of 7.39 ± 0.25–35.29 ± 2.49 μM with IC₅₀ values for AChE and 14.38 ± 0.66–58.02 ± 4.94 μM for BuChE as compared with galantamine, which used as a positive control. For α‐glucosidase, all compounds had stronger inhibition action than acarbose according to the IC₅₀ values. The IC₅₀ values of N? Co and N? Mn were found to be 3.05 ± 0.10 and 15.82 ± 1.85 μM, respectively. The results of cytotoxicity showed that the IC₅₀ values were above 100 μM showing the compounds had low cytotoxic action against SH‐SY5Y cell line for 24 h. Overall, carbazole substituted nonperipheral compounds can be considered as a potential agent for the treatment of Alzheimer's diseases and diabetes mellitus.     

Synthesis,Antiproliferative, and c‐Src Kinase Inhibitory Activities of 4‐Oxo‐4H‐1‐benzopyran Derivatives

A new class of 4‐oxo‐4H‐1‐benzopyran derivatives were synthesized and their antiproliferative activity examined against a panel of three human cancer cell lines, that is, breast carcinoma (MDA‐MB‐468), ovarian adenocarcinoma (SK‐OV‐3), and colorectal adenocarcinoma (HT‐29). Two compounds, that is, 3‐hexyl‐7,8‐dihydroxy‐4‐oxo‐4H‐1‐benzopyran and (E)‐ethyl 3‐(7‐methoxy‐4‐oxo‐4H‐1‐benzopyran‐3‐yl)acrylate were found to be potent against all three cancer cell lines studied at 50 μM concentration. Also, the inhibitory potency of the compounds was evaluated against active Src kinase. A few of these compounds exhibited modest Src kinase inhibitory activity (IC₅₀ = 52–57 μM). Structure‐activity relationship studies with respect to the nature and position of substituents on the lead compounds could be further exploited for the design and development of more potent antiproliferative agents and/or Src kinase inhibitors.     

Synthesis,anti‐proliferative activity,SAR, and kinase inhibition studies of thiazol‐2‐yl‐ substituted sulfonamide derivatives

A series of novel thiazol‐2‐yl substituted‐1‐sulfonamide derivatives were synthesized from anilines. This involved the coupling of sulfonyl chlorides with thiazol amine to obtain the final compounds 7a – 7j and 8a – 8j . All synthesized compounds were screened for anticancer activity against MCF‐7, HeLa, A‐549, and Du‐145 cancer cell lines by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay. Preliminary bioassay suggests that most of the compounds show anti‐proliferation to different degrees, with doxorubicin used as positive control. The synthesized compounds show IC₅₀ values in the range 2.74–8.17 μM in the different cell lines. The compounds 7d , 7e , 8a , 8d , and 8e were active compared to doxorubicin. The compounds having butyl and pantyl chains were more active than their lower and higher carbon chains and also their ring counterparts.     

Synthesis and Cytotoxicity in Vitro of N‐Aryl‐4‐(tert‐butyl)‐5‐(1H‐1,2,4‐triazol‐1‐yl)thiazol‐2‐amine

A series of novel N‐aryl‐4‐(tert‐butyl)‐5‐(1H‐1,2,4‐triazol‐1‐yl)thiazol‐2‐amines synthesized in a green way. H₂O₂‐NaBr Brominating circulatory system was used in the synthesis of the key intermediate in a mild condition. All of the target compounds were confirmed by ¹H NMR and elemental analysis and tested for their cytotoxicity against two different human cancer cell lines. The cytotoxicity assay revealed that some of the title compounds showed moderate to strong cytotoxic activities. Compound 2i was the most potent compound with the IC₅₀ values of 9 μM against Hela cells and 15 μM against Bel–7402 cells, respectively.     

Synthesis of 3‐[4‐Acyl‐2‐(1‐methoxy‐1‐methylethyl)morpholin‐3‐yl]‐benzonitriles as Novel Potassium Channel Openers

Potassium channel openers (KCO's) have been demonstrated to possess potent relaxant‐activity on smooth muscle. Tissue‐selective KCO's may find use in the treatment of a variety of diseases, such as hypertension, asthma, and urinary incontinence. We have previously reported a series of 1,9‐dioxa‐4‐aza‐phenanthrene‐6‐carbonitriles, including compounds 2 & 3 , as bladder‐selective KCO's. As a continuation of our efforts, we have designed 3‐[4‐acyl‐2‐(1‐methoxy‐1‐methylethyl)morpholin‐3‐yl]‐benzonitriles as ring‐opened analogs of compounds 2 & 3 . In this report, we describe the efficient construction of the novel 2,3‐disubstituted morpholine structure, as represented by the synthesis of compounds 4‐7 . Compounds 4‐7 showed potent and selective relaxant‐activity on rat bladder detrusor strip preparation. In this series, the most potent derivatives are Boc‐substituted analogs 4 & 6 (IC₅₀ = 3.9 and 2.9 μM, respectively).     

Synthesis and evaluation of new pyrazoline‐thiazole derivatives as monoamine oxidase inhibitors

A novel series of 1,3,5‐trisubstituted‐2‐pyrazoline derivatives ( 4a ‐ 4k ) was synthesized and their chemical structures characterized by ¹H NMR, ¹³C NMR, and mass spectroscopy. These compounds were evaluated as inhibitors for of type A and type B monoamine oxidase (MAO) enzymes. The most common inhibitors of MAO enzymes used to treat depression and anxiety such as selegiline and moclobemide drugs were used as reference agents. A result of biological evaluation of these compounds revealed compounds 4c , 4d , and 4? as potent and selective MAO A inhibitors. The most active compound 4? , which is 2,4‐dimethoxy at phenyl ring, showed strong inhibitory activity at MAO A (IC₅₀ of 0.0445 ± 0.0018μM). Furthermore, compounds 4c and 4d showed significant inhibition profile on MAO A with the IC₅₀ values 0.1423 ± 0.0051μM and 0.2148 ± 0.0067μM, respectively.     

Chemical Constituents of the Endophytic Fungus Hypoxylon sp. 12F0687 Isolated from Taiwanese Ilex formosana

Bioassay‐guided fractionation of an AcOEt‐soluble fraction of the liquid fermentation of an endophytic fungus Hypoxylon sp. BCRC 12F0687 associated with the root of Taiwanese Ilex formosana (Aquifoliaceae) resulted in the isolation of two new compounds, i.e., one benzenoid, hypoxyphenone ( 1 ), and one azaphilone derivative, hypoillexidiol ( 2 ), two metabolites isolated for the first time from natural source, (?)‐(3S)‐3‐hydroxy‐3‐methyloxindole ( 3 ) and (+)‐vermelone ( 4 ), along with twelve previously identified compounds, 5 – 16 . Their structures were determined through in‐depth spectroscopic and mass‐spectrometric analyses. The effects of some isolates on the inhibition of NO and IL‐6 production in lipopolysaccharide‐activated RAW 264.7 murine macrophages were evaluated. Of the isolates, 2 and 3 exhibited potent anti‐NO production activity, with IC₅₀ values of 17.5±1.8 and 24.7±1.6 μM , respectively, compared to that of quercetin, an iNOS inhibitor with an IC₅₀ value of 35.9±1.7 μM . Compounds 2, 4, 5 , and 12 also showed moderate inhibition of IL‐6 production, with IC₅₀ values ranging from 27.2±1.8 to 35.3±5.8 μM . This is the first report on an oxindole metabolite from the genus Hypoxylon.     

Synthesis and Cytotoxicity of 6‐Pyrrolidinyl‐2‐(2‐Substituted Phenyl)‐4‐Quinazolinones

In our continuing search for potential anticancer candidates, 2‐(3‐methoxyphenyl)‐6‐pyrrolidinyl‐4‐quinazolinone ( JJC‐1 ) was selected as the lead compound. Starting 5‐pyrrolidinyl‐2‐aminobenzamide was prepared using standard methodology from 5‐chloro‐2‐nitrobenzoic acid by reaction with SOCl₂, NH₃, pyrrolidine, and H₂. The starting benzamide then was reacted with 2‐substituted benzaldehyde or benzoyl chloride in N,N‐dimethylacetamide (DMAC) in the presence of NaHSO₃ at 150 °C. Thermal cyclodehydration/dehydrogenation gave the target 6‐pyrrolidinyl‐2‐(2‐substituted phenyl)‐4‐quinazolinones ( 15–22 ). These target compounds were assayed for their cytotoxicity in vitro against six cancer cell lines, including human monocytic leukemia cells (U937), mouse monocytic leukemia cells (WEHI‐3), human hepatoma cells (HepG2, Hep3B) and human lung carcinoma cells (A549, CH27). Most of them exhibited significant cytotoxic effect toward U937 and WEHI‐3 cells, with EC₅₀ values ranging from 0.30 to 10.10 μM. Compound 19 was investigated further for its action mechanisms. Preliminary findings indicated that compound 19 induced G2/M arrest and apoptosis on U937 cells.     

Inhibitors of the Bifunctional 2‐C‐Methyl‐d‐erythritol 4‐Phosphate Cytidylyl Transferase/2‐C‐Methyl‐d‐erythritol‐2,4‐cyclopyrophosphate Synthase (IspDF) of Helicobacter pylori

A library of over 103 thousand compounds was screened for inhibitors of the IspD domain (2‐C‐methyl‐d ‐erythritol 4‐phosphate cytidylyl transferase domain) of the bifunctional IspDF protein from Helicobacter pylori using a photometric assay. Around 300 compounds showed IC₅₀ values below 100 μm , and three compounds had IC₅₀ values below 1 μm . A few IspD inhibitors could also inhibit the IspF domain (2‐C‐Methyl‐d ‐erythritol‐2,4‐cyclopyrophosphate synthase) of the IspDF protein. The most potent IspD inhibitors were tested as growth inhibitors of H. pylori. Several compounds showed inhibition of bacterial growth with IC₅₀ in the single‐digit μm range. The most potent growth inhibitor had an IC₅₀ value of 3.4 μm . The most potent growth inhibitor without measurable effect on eukaryotic cell viability had an IC₅₀ value of 7.2 μm .     

Synthesis,Antiproliferative, and Antiplatelet Activities of Oxime‐Containing 3,4‐Dihydroquinolin‐2(1H)‐One Derivatives

Some oxime‐containing 3,4‐dihydroquinolin‐2(1H)‐one derivatives were synthesized and evaluated for their antiplatelet and antiproliferative activities. These compounds were synthesized via alkylation of hydroxyl precursors followed by the reaction with NH₂OH. The preliminary assays indicated that (Z)‐7‐[2‐(4‐fluorophenyl)‐2‐(hydroxyimino)ethoxy]‐3,4‐dihydroquinolin‐2(1H)‐one (13c) is the most active against U46619 induced platelet aggregation with an IC₅₀ value of 3.51 μM. For the inhibition of AA‐induced aggregation, (E)‐6‐[2‐(hydroxyimino)propoxy]‐3,4‐dihydroquinolin‐2(1H)‐one (15 ) is the most potent with an IC₅₀ value of 1.85 μM. These oxime‐containing 3,4‐dihydroquinolin‐2(1H)‐one derivatives were inactive against thrombin induced platelet aggregation with an IC₅₀ value of greater than 26.78 μM. For the antiproliferative activity, most of these oxime‐containing 3,4‐dihydroquinolin‐2(1H)‐one derivatives were inactive while (Z)‐7‐[2‐(hydroxyimino)‐2‐(naphthalen‐2‐yl)ethoxy]‐3,4‐dihydroquinolin‐2(1H)‐one (13a) exhibited only marginal activities with GI₅₀ value of 7.63, 7.34 and 6.36 μM against the growth of NPC‐TW01, NCI‐H661, and Jurkat respectively.     

Synthesis and Cytotoxic Activity of 1‐{3‐[1‐(5‐Organylsilylfuran‐2‐yl)silinan‐1‐yl]propyl}amines and Some Trimethylgermyl Analogues

New highly cytotoxic 1‐{3‐[1‐(5‐organylsilyl‐furan‐2‐yl)silinan‐1‐yl]propyl}amines and some trimethylgermyl analogues (IC₅₀ 1–7 μg mL^?1) have been synthesized by a hydrosilylation reaction of aliphatic and heterocyclic N‐allylamines in the presence of Speier’s catalyst. The effects of the silacycle, the element‐organic substituent in position 5 of the furan ring, and the structure of the amine on the cytotoxicity of the new compounds have been studied.     

Methyl Pothoscandensate,a New ent‐18(4→3)‐Abeokaurane from Pothos scandens

Methyl pothoscandensate ( 1 ), a new molecular skeleton of ent‐18(4→3)‐abeokaurane, along with eight known compounds was isolated from the whole plant of Pothos scandens. The structure of the new compound was established by spectroscopic techniques and confirmed by single‐crystal X‐ray diffraction. The inhibitory activity of selected compounds against porcine respiratory and reproductive syndrome virus (PRRSV) was measured by the cytopathic effect (CPE) method. Compound 1 showed weak effect on PRRSV with an IC₅₀ value of 40.3±8.3 μM (TI=15.7).     

Design,synthesis of (Z)‐3‐benzyl‐5‐((1‐phenyl‐3‐(3‐((1‐ substituted phenyl‐1H‐1,2,3‐triazol‐4‐yl)methoxy)phenyl)‐1H‐pyrazol‐4‐yl)methylene)thiazolidine‐2,4‐dione analogues as potential cytotoxic agents

In an attempt to achieve promising cytotoxic agents, a series of new (Z)‐3‐benzyl‐5‐((1‐phenyl‐3‐(3‐((1‐substituted phenyl‐1H‐1,2,3‐triazol‐4‐yl)methoxy)phenyl)‐1H‐pyrazol‐4‐yl)methylene)thiazolidine‐2,4‐diones 10 a‐n were designed, synthesized, and characterized by ¹H NMR, ¹³C NMR, IR, and ESI‐MS techniques. These compounds synthesized from appropriate reaction procedures with better yields. All the novel synthesized compounds 10a‐n were evaluated for their cytotoxic activity against the MCF‐7 cell line (Human breast cancer cell line) at different concentrations of 0.625, 1.25, 2.5, 5, and 10 μM, respectively. The cytotoxic evaluation assay is presented in terms of IC₅₀ values and percentage cell viability reduction compared against standard drug cisplatin. Among all novel synthesized compounds 10a‐n , some of the representative analogues particularly 10g and 10e exhibit remarkable cytotoxic activity with IC₅₀ values 0.454 and 0.586 μM, comparable to that of the standard drug cisplatin, and some analogues 10d , 10f , 10k, and 10m also have shown significant activity.     

Bisubstrate Inhibitors for the Enzyme Catechol O‐Methyltransferase (COMT): Dramatic Effects of Ribose Modifications on Binding Affinity and Binding Mode

Inhibition of the enzyme catechol O‐methyltransferase (COMT) is of significant interest in the therapy of Parkinson's disease. Described herein are structural analogs of the potent bisubstrate inhibitor (?)‐ 1 (IC₅₀=9 nM ; Table 1) for COMT, with target modifications of the central ribose moiety. Their synthesis involves, as key intermediates, adenosine derivatives, which are transformed to the potential bisubstrate inhibitors by a similar sequence of six steps (Schemes 1–4). The compounds were submitted to an enzymatic assay for determination of their in vitro inhibitory activity against COMT, and the inhibition mechanism with respect to the binding side of the cofactor S‐adenosylmethionine (SAM) was analyzed by kinetics measurements (Fig. 3). Both binding affinity and binding mode were exceedingly sensitive towards modifications of the ribose moiety (Table 1). Removal of the 2′‐OH group upon changing from (?)‐ 1 to (?)‐ 2 (IC₅₀=28 μM ) led to a reduction in binding affinity by more than three orders of magnitude. At the same time, competitive inhibition kinetics with respect to the SAM binding site was maintained, thereby supporting a bisubstrate binding mode. Unlike (?)‐ 2 , the dideoxyribose inhibitor (?)‐ 3 (IC₅₀=3 μM ) showed a mixed and the cyclopentane derivative (+)‐ 4 (IC₅₀=1 μM ) an uncompetitive inhibition mechanism with respect to the SAM binding site. In the complex of the latter, the adenine‐substituted cyclopentane ring orients most probably towards the surface of the enzyme into the surrounding solution. The enantiomeric compounds (?)‐ 5 (IC₅₀=43 μM ) and (+)‐ 5 (IC₅₀=141 μM ), wherein the ribose had been replaced by a pyrrolidine ring, showed only low binding affinity.