High-affinity, selective σ ligands of the 1,2,3,4-tetrahydro-1,4'-silaspiro[naphthalene-1,4'-piperidine] type: syntheses, structures, and pharmacological properties

The 1'-organyl-1,2,3,4-tetrahydrospiro[naphthalene-1,4'-piperidine] derivatives 1?a-4?a [for which organyl=benzyl (1?a), 4-methoxybenzyl (2?a), 2-phenylethyl (3?a), or 3-methylbut-2-enyl (4?a)] are high-affinity, selective σ? ligands. The corresponding sila-analogues 1?b-4?b (replacement of the carbon spirocenter with a silicon atom) were synthesized in multistep syntheses, starting from dichlorodivinylsilane, and were isolated as the hydrochlorides 1?b?HCl-4?b?HCl. Compounds 1?a?HCl-4?a?HCl and 1?b?HCl-4?b?HCl were structurally characterized by NMR spectroscopy (1H, 13C, 2?Si) in solution, and the C/Si analogues 3?a?HCl and 3?b?HCl were studied by single-crystal X-ray diffraction. These structural investigations were complemented by computational studies. The σ? and σ? receptor affinities of the C/Si pairs 1?a/1?b-4?a/4?b were studied with radioligand binding assays. The σ? receptor affinity of the silicon compounds 1?b-4?b is slightly higher than that of the corresponding carbon analogues 1?a-4?a. Because affinity for the σ? receptor is decreased by the C/Si exchange, the σ?/σ? selectivity of the silicon compounds is considerably improved, indicating that the C→Si switch strategy is a powerful tool for modulating both pharmacological potency and selectivity.     

Novel silicon-containing analogues of the retinoid agonist bexarotene: syntheses and biological effects on human pluripotent stem cells

Twofold sila‐substitution (C/Si exchange) of the clinically used RXR‐selective retinoid agonist bexarotene leads to disila‐bexarotene, which displays pharmacological potency similar to that of the parent carbon compound, as shown in a HeLa‐cell‐based RXR assay. Formal exchange of the SiCH₂CH₂Si group in disila‐bexarotene with a SiCH₂Si or SiOSi moiety leads to the disila‐bexarotene analogues 8 and 9 . The silicon compounds 8 and 9 were synthesized in multistep syntheses, starting from HC?C(CH₃)₂SiCH₂Si(CH₃)₂C?CH and HC?C(CH₃)₂SiOSi(CH₃)₂C?CH, respectively. The key step in the syntheses of 8 and 9 is a cobalt‐catalyzed [2+2+2] cycloaddition reaction that affords the 1,3‐disilaindane and 2‐oxa‐1,3‐disilaindane skeletons. Disila‐bexarotene and its analogues 8 and 9 were studied for their biological effects relative to all‐trans retinoic acid in cultured human pluripotent stem cells. The parent carbon compound bexarotene was included in some of these biological studies. Although the silicon‐containing bexarotene analogues disila‐bexarotene, 8 , and 9 appear not to regulate the differentiation of TERA2.cl.SP12 stem cells, preliminary evidence indicates that these compounds may possess enhanced functions over the parent compound bexarotene, such as induction and regulation of cell death and cell numbers. The biological data obtained indicate that bexarotene, contrary to the silicon‐containing analogues disila‐bexarotene, 8 , and 9 , may partially act to induce cell differentiation.     

Functional and Structural Insights into Human PPARα/δ/γ Subtype Selectivity of Bezafibrate,Fenofibric Acid,and Pemafibrate

Among the agonists against three peroxisome proliferator-activated receptor (PPAR) subtypes, those against PPARα (fibrates) and PPARγ (glitazones) are currently used to treat dyslipidemia and type 2 diabetes, respectively, whereas PPARδ agonists are expected to be the next-generation metabolic disease drug. In addition, some dual/pan PPAR agonists are currently being investigated via clinical trials as one of the first curative drugs against nonalcoholic fatty liver disease (NAFLD). Because PPARα/δ/γ share considerable amino acid identity and three-dimensional structures, especially in ligand-binding domains (LBDs), clinically approved fibrates, such as bezafibrate, fenofibric acid, and pemafibrate, could also act on PPARδ/γ when used as anti-NAFLD drugs. Therefore, this study examined their PPARα/δ/γ selectivity using three independent assays—a dual luciferase-based GAL4 transactivation assay for COS-7 cells, time-resolved fluorescence resonance energy transfer-based coactivator recruitment assay, and circular dichroism spectroscopy-based thermostability assay. Although the efficacy and efficiency highly varied between agonists, assay types, and PPAR subtypes, the three fibrates, except fenofibric acid that did not affect PPARδ-mediated transactivation and coactivator recruitment, activated all PPAR subtypes in those assays. Furthermore, we aimed to obtain cocrystal structures of PPARδ/γ-LBD and the three fibrates via X-ray diffraction and versatile crystallization methods, which we recently used to obtain 34 structures of PPARα-LBD cocrystallized with 17 ligands, including the fibrates. We herein reveal five novel high-resolution structures of PPARδ/γ–bezafibrate, PPARγ–fenofibric acid, and PPARδ/γ–pemafibrate, thereby providing the molecular basis for their application beyond dyslipidemia treatment.     

Mapping the Melatonin Receptor. 8. Selective MT2 Agonists Derived from 5,6-Dihydroindolo[2,1-a]isoquinolines and Related Systems

A series of substituted indolo[2,1-a]isoquinolines and indolo[1,2-a]benzoxazines have been prepared, as melatonin analogues, to investigate the nature of the binding site of the melatonin receptor. Agonist and antagonist potency of all the analogues was measured using the [35S]GTPγS binding assay protocol. The binding affinity of the analogues were measured by competition binding studies against the human MT1 (hMT1) and MT2 (hMT2) receptors stably transfected in Chinese Hamster Ovarian (CHO) cells, using 2-[¹²⁵I]-iodomelatonin, as a ligand. N-Acetyl 2-(10-methoxy-5,6-dihydroindolo[2,1-a]isoquinolin-12-yl)propyl-1-amine (12 a) binds strongly to both the hMT1 and hMT2 receptors, and shows a preference for the hMT2, as does its propanamido counterpart 12 b . The introduction of two methyl groups into their side chain, analogues 15 a and 1 5 b , leads to antagonism, in the case of the former, and drastically diminishes its hMT1 binding; an analogous profile is seen for 15 b , which, however, is a partial agonist. Introduction of chlorine or methoxy groups into ring 4 gives compounds, that are weakly binding, with a preference for MT2. Substitution of oxygen for carbon at position 5 gives the indolo[1,2-c]benzoxazines 33 , 36 a and b , that bind strongly to the human receptors, 33 , 36 b being potent agonists at the melatonin receptors, but do not discriminate between hMT1 and hMT2.     

Development of selective estrogen receptor modulator (SERM)-like activity through an indirect mechanism of estrogen receptor antagonism: defining the binding mode of 7-oxabicyclo[2.2.1]hept-5-ene scaffold core ligands

Previously, we discovered estrogen receptor (ER) ligands with a novel three-dimensional oxabicyclo[2.2.1]heptene core scaffold and good ER binding affinity act as partial agonists via small alkyl ester substitutions on the bicyclic core that indirectly modulate the critical switch helix in the ER ligand binding domain, helix 12, by interactions with helix 11. This contrasts with the mechanism of action of tamoxifen, which directly pushes helix 12 out of the conformation required for gene activation. We now report that a much larger substitution can be tolerated at this position of the bicyclic core scaffold, namely a phenyl sulfonate group, which defines a novel binding epitope for the estrogen receptor. We prepared an array of 14 oxabicycloheptene sulfonates, varying the phenyl sulfonate group. As with the parent compound, 5,6-bis-(4-hydroxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonic acid phenyl ester (OBHS), these compounds showed preferential affinity for ERα, and the disposition and size of the phenyl substituents were important determinants of the binding affinity and selectivity of these compounds, with those having ortho substituents giving the highest, and para substituents the lowest affinities for ERα. A few analogues exhibit ERα binding affinities that are comparable to or, in the case of the ortho-chloro analogue, higher than that of OBHS itself. In cell-based studies, we found several compounds with activity profiles comparable to tamoxifen, but acting entirely as indirect antagonists, allosterically interfering with recruitment of coactivator proteins to the receptor. Thus, the OBHS binding epitope represents a novel approach to the development of estrogen receptor antagonists via an indirect mechanism of antagonism.     

Action of acrylonitrile on 4-cyano- and 4-carbethoxy pyridazin-3(2H)-ones and their 3-mercapto derivatives. A novel Synthesis of Pyrano and Thiinopyridazines

Reaction of acrylonitrile with 4-cyano-5,6-diphenyl pyridazin-3(2H)-one and 3(2H)-thione derivative ( 1a, b ) at elevated temperature gave 7H-5-amino-6-cyano-3,4-diphenylpyrano and thiino [2,3-c] pyridazines ( 2a, b ), respectively. However, the reaction of 4-carbethoxy pyridazine derivatives ( 1c, d ) with the same reagent, under the same conditions afforded 6H, 7H-6-cyano-3,4-diphenyl-5-oxopyrano ( 3a ) and thiino [2,3-c] pyridazine ( 3b ), respectively. In addition, treatment of ( 1a, c ) and ( 1b, d ) with acrylonitrile ar reflux in alkaline medium give the respective 3-(2′-cyanoethyloxo) ( 7a, c ) and 3-2′-cyanoethylthio ( 7b, d ) pyridazine derivatives. Prolonged alkaline hydrolysis of either ( 1a, c ) or ( 7a, c ) yielded the same product ( 8a ). Also hydrolysis of ( 1b, d ) and ( 7b, d ) afforded one and the same product ( 8b ). The structures of the products were assigned on the basis of satisfactory analytical and spectroscopic data.     

Sila-haloperidol, a silicon analogue of the dopamine (D2) receptor antagonist haloperidol: synthesis, pharmacological properties, and metabolic fate

Haloperidol (1 a), a dopamine (D(2)) receptor antagonist, is in clinical use as an antipsychotic agent. Carbon/silicon exchange (sila-substitution) at the 4-position of the piperidine ring of 1 a (R(3)COH --> R(3)SiOH) leads to sila-haloperidol (1 b). Sila-haloperidol was synthesized in a new multistep synthesis, starting from tetramethoxysilane and taking advantage of the properties of the 2,4,6-trimethoxyphenyl unit as a unique protecting group for silicon. The pharmacological profiles of the C/Si analogues 1 a and 1 b were studied in competitive receptor binding assays at D(1)-D(5), sigma(1), and sigma(2) receptors. Sila-haloperidol (1 b) exhibits significantly different receptor subtype selectivities from haloperidol (1 a) at both receptor families. The C/Si analogues 1 a and 1 b were also studied for 1) their physicochemical properties (log D, pK(a), solubility in HBSS buffer (pH 7.4)), 2) their permeability in a human Caco-2 model, 3) their pharmacokinetic profiles in human and rat liver microsomes, and 4) their inhibition of the five major cytochrome P450 isoforms. In addition, the major in vitro metabolites of sila-haloperidol (1 b) in human liver microsomes were identified using mass-spectrometric techniques. Due to the special chemical properties of silicon, the metabolic fates of the C/Si analogues 1 a and 1 b are totally different.     

Cytotoxic Activity of Silyl- and Germyl-Substituted 4,4-Dioxo-3a,6a-Dihydrothieno[2,3-d]isoxazolines-2

The [2+3] dipolar cycloaddition of nitrile oxides to the double C = C bonds of thiophene-1, 1-dioxides leads to formation of the fused isoxazolines-2 (1, 2). Tumor growth inhibition of these compounds strongly depends on the nature of group IV A element increasing from slightly active tert-butyl derivatives to silicon and germanium containing analogues. The products of benzonitrile oxide cycloaddition have greater cytotoxic effect than the compounds obtained from the cycloaddition reaction of 2, 5-disubstituted thiophene-1, 1-dioxides with acetonitrile oxide. Fused silyl substituted isoxazolines-2 are stronger NO-inducers than their germyl and tert-butyl analogues.     

N-取代苯并噁唑啉酮及N-取代苯并噁嗪啉酮类化合物的合成和生物活性

采用邻氨基酚为原料合成了一系列N-取代苯并噁唑啉酮类化合物和N-取代的苯并噁嗪啉酮类化合物,其化学结构经过1H核磁共振及元素分析确证。初步的生物活性试验结果表明,N-取代苯并噁唑啉酮类化合物具有一定的杀虫杀菌活性,其中化合物3b、4b、14b、19b在50mg/L浓度下对淡色库蚊的杀死率为100%,化合物20b、21b、24b、25b、26b、27b、30b在1000mg/L浓度下对朱砂叶螨的杀死率均达95%以上;N-取代苯并噁嗪啉酮类化合物具有良好的除草活性,如化合物3d,5d,6d,7d和8d在浓度为100mg/L时,对苋菜Ambrosia tricolor Linn的抑制率达90%。     

Syntheses of 4-aroyl and 4-Disubstituted Hydroxymethyl-pyridazin-3(2H)-ones and Their 3-Mercapto Derivatives: Synthesis of 1,3-Dithiano[4,5-c]pyridazine as a New Ring System

A number of 4-aroylpyridazin-3(2H)-ones ( 2a – c ), 4-disubstituted hydroxymethyl-pyridazin-3(2H)-ones ( 3a – c ) and their thio derivatives ( 3d – f ) have been prepared from different Grignard reagents and 5,6-diphenyl-4-cyano( 1a ), 4-carbethoxy ( 1b )pyridazin-3(2H)-ones and 3-mercapto derivatives ( 1c and d ). The structures of the compounds prepared were inferred from their elemental analysis, spectral data and from the identity of some of them with authentic samples.     

Chemistry and Pharmacology of Nicotinic Ligands Based on 6‐[5‐(Azetidin‐2‐ylmethoxy)pyridin‐3‐yl]hex‐5‐yn‐1‐ol (AMOP‐H‐OH) for Possible Use in Depression

AMOP‐H‐OH (sazetidine‐A; 6‐[5‐(azetidin‐2‐ylmethoxy)pyridin‐3‐yl]hex‐5‐yn‐1‐ol) and some sulfur‐bearing analogues were tested for their activities in vitro against human α4β2‐, α4β4‐, α3β4*‐ and α1*‐nicotinic acetylcholine receptors (nAChRs). AMOP‐H‐OH was also assessed in an antidepressant efficacy model. AMOP‐H‐OH and some of its analogues have high potency and selectivity for α4β2‐nAChRs over other nAChR subtypes. Effects are manifested as partial agonism, perhaps reflecting selectivity for high sensitivity (α4)₃(β2)₂‐nAChRs. More prolonged exposure to AMOP‐H‐OH and its analogues produces inhibition of subsequent responses to acute challenges with full nicotinic agonists, again selectively for α4β2‐nAChRs over other nAChR subtypes. The inhibition is mediated either via antagonism or desensitization of nAChR function, but the degree of inhibition of α4β2‐nAChRs is limited by the partial agonist activity of the drugs. Certain aspects of the in vitro pharmacology suggest that AMOP‐H‐OH and some of its analogues have a set of binding sites on α4β2‐nAChRs that are distinct from those for full agonists. The in vitro pharmacological profile suggests that peripheral side effects of AMOP‐H‐OH or its analogues would be minimal and that their behavioral effects would be dominated by central nAChR actions. AMOP‐H‐OH also has profound and high potency antidepressant‐like effects in the forced swim test. The net action of prolonged exposure to AMOP‐H‐OH or its analogues, as for nicotine, seems to be a selective decrease in α4β2‐nAChR function. Inactivation of nAChRs may be a common neurochemical endpoint for nicotine dependence, its treatment, and some of its manifestations, including relief from depression.     

3—碘—苯并吡喃—4—酮与2—硫代嘧啶类的Michael加成反应

报道了具有α，β－不饱和羰基的３－碘－苯并吡喃－４－酮（１）与２－硫代嘧啶发生Ｍｉｃｈａｅｌ加成反应，合成出４个２－（２－羟苯甲酰基）－５－氧－５Ｈ－噻唑并［２，３－ｂ］嘧啶的衍生物。这些化合物结构经核磁共振光谱、紫外吸收光谱、红外光谱和元素分析均予以证实。     

Synthesis, receptor binding, and CNS pharmacological studies of new thyrotropin-releasing hormone (TRH) analogues

As part of our search for selective and CNS‐active thyrotropin‐releasing hormone (TRH) analogues, we synthesized a set of 44 new analogues in which His and pGlu residues were modified or replaced. The analogues were evaluated as agonists at TRH‐R1 and TRH‐R2 in cells in vitro, and in vivo in mice for analeptic and anticonvulsant activities. Several analogues bound to TRH‐R1 and TRH‐R2 with good to moderate affinities, and are full agonists at both receptor subtypes. Specifically, analogue 21 a (R=CH₃) exhibited binding affinities (K_i values) of 0.17 μM for TRH‐R1 and 0.016 μM for TRH‐R2; it is 10‐fold less potent than TRH in binding to TRH‐R1 and equipotent with TRH in binding to TRH‐R2. Compound 21 a , the most selective agonist, activated TRH‐R2 with a potency (EC₅₀ value) of 0.0021 μM , but activated TRH‐R1 at EC₅₀=0.05 μM , and exhibited 24‐fold selectivity for TRH‐R2 over TRH‐R1. The newly synthesized TRH analogues were also evaluated in vivo to assess their potencies in antagonism of barbiturate‐induced sleeping time, and several analogues displayed potent analeptic activity. Specifically, analogues 21 a , b and 22 a , b decreased sleeping time by nearly 50 % more than TRH. These analogues also displayed potent anticonvulsant activity and provided significant protection against PTZ‐induced seizures, but failed to provide any protection in MES‐induced seizures at 10 μmol kg^?1. The results of this study provide evidence that TRH analogues that show selectivity for TRH‐R2 over TRH‐R1 possess potent CNS activity.     

C3 Halogen and C8′′ Substituents on Stilbene Arotinoids Modulate Retinoic Acid Receptor Subtype Function

The synthesis and biological evaluation of the entire series of C3‐halogenated derivatives and bulkier substituents at the C8′′ position of the parent stilbene‐based RARβ‐selective agonist BMS641 4 c was undertaken. The synthesis uses an E‐selective Horner–Wadsworth–Emmons (HWE) condensation of C8‐substituted C5‐dimethyl dihydronaphthaldehyde and the benzylic phosphonates derived from the C3‐halogenated benzoates to construct the stilbene skeleton. Transactivation studies revealed the synergistic effect of small halogen atoms at C3 (F, Cl) and the moderately bulky phenyl group at C8′′ (in 4 b and 4 c ) to achieve RARβ selectivity. Our results, supported by computational studies, provide a structural rationale for the mixed agonist–antagonist activities of these arotinoids, which are potent agonists of the RARβ subtype and antagonists of the RARα paralogue. Moreover, transitions from partial agonists to inverse agonists and antagonists can be accomplished with the incorporation of the same halogen atoms into the structures of known modulators BMS701 ( 5 a ) and BMS493 ( 6 a ), which have bulkier substituents than phenyl (p‐tolyl and phenylethynyl, respectively) at C8′′. Conversely, incorporation of halogen atoms in 6 a converted the ligand from an RARβ inverse agonist ( 6 b ) to an antagonist ( 6 c ) or an agonist ( 6 d ). Amazingly, 6 a – c commonly acted as inverse agonists for RARα, while 6 d and 6 e acted as regular RARα antagonists, not affecting co‐repressor interaction. In the case of the mixed agonist/antagonist 5 a , C3‐halogenation yields inverse RARα and RARβ agonists ( 5 b – d ) with the exception of iodinated 5 e , which is a regular antagonist for both these receptors. Because RARβ gene expression is frequently deleted or epigenetically silenced in several tumor cells, the novel repertoire of receptor and function‐selective RAR agonists, mixed agonist/antagonists, regular antagonists, and inverse agonists will be useful in the elucidation of the mechanism of tumor suppression by retinoids.     

The Discovery of LML134, a Histamine H3 Receptor Inverse Agonist for the Clinical Treatment of Excessive Sleep Disorders

Histamine H3 receptor (H3R) inverse agonists that have been in clinical trials for the treatment of excessive sleep disorders, have been plagued with insomnia as a mechanism-based side effect. We focused on the identification of compounds that achieve high receptor occupancy within a short time, followed by rapid disengagement from the receptor, a target profile that could provide therapeutic benefits without the undesired side effect of insomnia. This article describes the optimization work that led to the discovery of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate ( 18 b , LML134).     

Synthesis and biological activity of metabolically stabilized cyclopentyl trisphosphate analogues of D-myo-Ins(1,4,5)P3

We describe the synthesis of four novel metabolically stabilized analogues of Ins(1,4,5)P(3) based on the known cyclopentane pentaol tris(phosphate) 2: tris(phosphorothioate) 3, tris(methylenephosphate) 4, tris(sulfonamide) 5, and tris(sulfate) 6. Of these analogues, only the tris(phosphorothioate) 3 and parent tris(phosphate) 2 bound to the type I InsP(3)R construct. In addition, both the tris(phosphorothioate) 3 and parent tris(phosphate) 2 elicited calcium release in MDA MB-435 breast cancer cells. The Ins(1,4,5)P(3) agonist activities of these two compounds can be rationalized on the basis of computational docking of the ligands to the binding domain of the type I InsP(3)R.     

2-取代-N-(7-氟-3,4-二氢-4-取代-3-氧-2H-苯并[b][1,4]噁嗪-6-基)乙酰胺类化合物的合成及除草活性

为了寻求高效、安全的除草活性的化合物,设计并合成了8个2-取代-N-(7-氟-3,4-二氢-4-取代-3-氧-2H-苯并[b][1,4]噁嗪-6-基)乙酰胺类化合物,其化学结构经IR,1HNMR,LC/MS等确证。初步生物活性测定结果表明,目标化合物的除草活性并不显著。     

以天然产物为先导化合物开发的农药品种(Ⅱ)--杀虫杀螨剂

概述了以天然产物为先导化合物进行的杀虫杀螨剂的创制研究以及开发的品种，涉及的化合物或类别如氨基甲酸酯、拟除虫菊酯、沙蚕毒素类似物、吡咯类、新烟碱类、保幼激素类似物、双酰肼(蜕皮激素类似物)、鱼藤酮类似物、二烯酰胺、季酮酸类、嘧螨酯、灭螨醌等，并对部分化合物的生物活性和创制经纬等进行了概述。     

Synthesis and Antiviral Evaluation of TriPPPro‐AbacavirTP,TriPPPro‐CarbovirTP,and Their 1′,2′‐cis‐Disubstituted Analogues

Herein we describe the synthesis of lipophilic triphosphate prodrugs of abacavir, carbovir, and their 1′,2′‐cis‐substituted carbocyclic analogues. The 1′,2′‐cis‐carbocyclic nucleosides were prepared by starting from enantiomerically pure (1R,2S)‐2‐((benzyloxy)methyl)cyclopent‐3‐en‐1‐ol by a microwave‐assisted Mitsunobu‐type reaction with 2‐amino‐6‐chloropurine. All four nucleoside analogues were prepared from their 2‐amino‐6‐chloropurine precursors. The nucleosides were converted into their corresponding nucleoside triphosphate prodrugs (TriPPPro approach) by application of the H‐phosphonate route. The TriPPPro compounds were hydrolyzed in different media, in which the formation of nucleoside triphosphates was proven. While the TriPPPro compounds of abacavir and carbovir showed increased antiviral activity over their parent nucleoside, the TriPPPro compounds of the 1′,2′‐cis‐substituted analogues as well as their parent nucleosides proved to be inactive against HIV.     

(S/R)-2-(2-(5-氟-2,4-二氧-3,4-二氢嘧啶-1(2H)-基)乙酰氨基)-3-(4-羟苯基)丙酸的合成及抗肿瘤活性

以1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐(EDCI)/1-羟基苯并三氮唑(HOBt)为缩合剂,5-氟尿嘧啶-1-基乙酸为中间体,分别与L-酪氨酸甲酯和D-酪氨酸乙酯通过液相偶联合成了(S)-2-(2-(5-氟-2,4-二氧-3,4-二氢嘧啶-1(2H)-基)乙酰氨基)-3-(4-羟苯基)丙酸甲酯和(R)-2-(2-(5-氟-2,4-二氧-3,4-二氢嘧啶-1(2H)-基)乙酰氨基)-3-(4-羟苯基)丙酸乙酯,水解后得到相应的酸对映体。所合成的化合物结构经1H NMR1、3C NMRI、R、MS及比旋光度等测试得以确证。四种化合物的体外抗肿瘤活性测试结果,说明该化合物的抗肿瘤具有一定的选择性,且R构型对抗肿瘤也起到了一定的作用。