含喹喔啉杨梅素衍生物的合成及生物活性

利用活性拼接原理, 将喹喔啉引入到杨梅素结构中, 合成了一系列含喹喔啉基团的杨梅素新型衍生物. 采用浊度法测试了目标化合物的体外抑菌活性, 结果表明, 目标化合物对柑橘溃疡病菌(X. Citri)和水稻白叶枯病菌(X. Oryzae)均表现出较好的抑制活性. 目标化合物对柑橘溃疡病菌的抑制活性(EC₅₀)均优于对照药叶枯唑和噻菌铜(EC₅₀分别为54.85和61.13 μg/mL), 其中化合物4o抑制活性(EC₅₀=11.17 μg/mL)最优; 目标化合物对水稻白叶枯病菌的抑制活性EC₅₀均优于对照药叶枯唑和噻菌铜(EC₅₀分别为148.20和175.47 μg/mL), 其中化合物4f抑制活性(EC₅₀=34.49 μg/mL)最优. 采用半叶枯斑法测试了目标化合物的抗烟草花叶病毒(TMV)活性, 结果表明, 所有目标化合物在浓度为500 mg/L时均有一定的抑制作用.     

1,4-双[3-脂肪基/苯基-1,2,4-三唑并[3,4-b]-1,3,4-噻二唑-6-基]芳基衍生物的合成与生物活性

在三氯氧磷催化下, 6种3-脂肪基-1,2,4-三唑(1a~1f)和3-苯基-1,2,4-三唑(1g)分别与对苯二甲酸和2-氨基-1,4-对苯二甲酸发生环化反应, 高产率合成了14种双枝三唑并噻二唑稠环衍生物(2和3), 并对其进行了结构表征及药物活性测试. 目标化合物对Cdc25B和PTP1B抑制活性筛选结果表明, 化合物2f, 3a和3g对Cdc25B有较高的抑制活性, IC₅₀值分别为(3.45±0.60), (0.69±0.10)和(1.52±0.19) μg/mL; 化合物3a和3b对PTP1B表现出较高的抑制活性, IC₅₀值分别为(0.98±0.13)和(2.00±0.16) μg/mL.     

直链淀粉-三[(S)-1-苯乙基氨基甲酸酯]手性固定相拆分布地奈德对映体及其制剂含量的测定

22R-布地奈德的药物活性比22S-布地奈德的强2~3倍,开发布地奈德对映体拆分和定量分析方法,可为其药物研发及质量控制提供重要依据。目前,主要以反相C₁₈固定相对布地奈德对映体进行拆分,而采用手性固定相对其进行拆分少有报道。通过考察固定相、流动相和柱温对布地奈德对映体拆分的影响,建立了基于直链淀粉-三[(S)-1-苯乙基氨基甲酸酯]手性固定相快速拆分和检测布地奈德对映体的高效液相色谱方法,其色谱条件如下:色谱柱为Chiralpak AS-RH色谱柱(150 mm×4.6 mm, 5.0 μm),流动相为乙腈-水(45∶55, v/v),柱温40 ℃,流速1.0 mL/min,二极管阵列检测器(DAD),检测波长246 nm,进样量10 μL。在该色谱条件下,布地奈德的两个对映体得到较好拆分,22R-布地奈德和22S-布地奈德的保留时间分别6.40 min和7.77 min,分离度为4.64; 22R-布地奈德和22S-布地奈德分别在各自范围内线性关系良好,相关系数(R²)均为0.9999,检出限分别为0.05 μg/mL和0.07 μg/mL,定量限分别为0.16 μg/mL和0.20 μg/mL; 4个添加水平的样品加标回收率为102.63%~104.17%,相对标准偏差(RSD)为0.08%~0.57%(n=6)。将该方法应用于1批次4个吸入用布地奈德混悬液实际样品进行检测,22R-布地奈德和22S-布地奈德的含量分别为283.15~284.63 μg/mL和259.86~261.51 μg/mL。该方法操作简便,分析时间短,重复性好,准确度高,可用于布地奈德对映体的拆分及其制剂的质量控制。     

QuEChERS结合超高效液相色谱-串联质谱法同时测定畜禽肉中44种食源性兴奋剂和6种孕激素

利用QuEChERS结合超高效液相色谱-串联质谱法建立了畜禽肉中44种兴奋剂和6种孕激素的检测技术。样品粉碎均质后加入内标,依次加入水和含0.5%乙酸的乙腈溶液振荡提取后,加入氯化钠和无水硫酸镁脱水离心,上清液采用PSA、C₁₈、中性氧化铝和无水硫酸镁分散固相萃取材料进行净化,净化液经氮气吹干,复溶后用超高效液相色谱-串联质谱仪测定。被测物采用ACQUITY BEH C₁₈(100 mm×2.1 mm, 1.7 μm)色谱柱,以0.1%甲酸-5 mmol/L乙酸铵水溶液和甲醇为流动相分离,在电喷雾正离子模式下,以多反应监测(MRM)方式采集,采用基质匹配标准曲线内标法定量分析。50个被测物包含6类化合物:β₂-激动剂类(19个)、β-阻断剂类(3个)、蛋白同化激素类(11个)、糖皮质激素类(8个)、利尿剂类(3个)、孕激素(6个)。所有被测物在各自的范围内线性关系良好,相关系数>0.99, β₂-激动剂类和β-阻断剂类的线性范围为0.1~20 μg/L,糖皮质激素类的线性范围为0.5~200 μg/L,蛋白同化激素类、孕激素类、利尿剂类的线性范围为0.2~50 μg/L。方法的定量限范围为0.1~0.4 μg/kg。在低、中、高3个浓度水平下的加标回收率试验中,50种目标化合物在鸡肉、猪肉、牛肉、羊肉中的平均回收率范围为50.3%~119.9%,相对标准偏差(RSD, n=6)范围为0.42%~15.1%。采用该法和国标方法(GB/T 21981-2008)同时对市售的9个肉样品(包括3个牛肉、3个猪肉、2个鸡肉、1个鸭肉)进行了比对检测,对检出的氢化可的松、可的松含量采用t检验进行统计学分析,结果表明,两种方法测得的数据没有显著性差异。采用该法测定了12个来自某养殖场的牛肉样品,结果共检出4种食源性兴奋剂,其中氢化可的松的含量范围为3.3~22.6 μg/kg,检出率为100%;可的松的含量范围为1.5~2.1 μg/kg,检出率为67%;雄烯二酮含量范围为0.7~1.2 μg/kg,检出率为17%;睾酮含量范围为0.6~1.5 μg/kg,检出率为42%。该法操作简单,准确灵敏,重复性好,适用于不同种类畜禽肉中食源性兴奋剂和孕激素的检测。     

双-β-咔啉衍生物的设计、合成及抗肿瘤活性

以去氢骆驼蓬碱为原料, 经过脱甲基、 烷基化等步骤, 合成了一系列双-β-咔啉衍生物. 目标化合物均经核磁共振谱(NMR)和质谱(MS)进行结构确证. 以顺铂为阳性对照药, 采用四甲基偶氮唑盐(MTT)法考察了目标化合物体外抗肿瘤(Bel-7402, 786-0, BGC-823, A375, 769-P和MCF7等6株细胞)活性. 结果表明, 化合物4g和4o与阳性对照药相比具有良好的抗肿瘤活性, 其半抑制浓度(IC₅₀)值均小于10 μmol/L. 初步构效关系研究表明, 当桥链亚甲基数目为8~10, β-咔啉环上9-丁基或9-异丁基取代时, 化合物的抗肿瘤活性较强.     

双核茂金属催化剂的合成、表征与应用

使用桥连配体锂盐与MCl₄络合, 合成了4个不同结构的双核茂金属化合物[μ,μ-(CH₂)₃]{[C(H)·(η⁵-C₅H₄)(η⁵-C₁₃H₈)](MCl₂)}₂[M=Zr or Ti](4, 5)和[μ,μ-(CH₂)₃]{[C(H)(η⁵-C₅H₄)(η⁵-C₉H₆)]·(MCl₂)}₂[M=Zr or Ti](6, 7), 配体和化合物都经过核磁氢谱(¹H NMR)、 碳谱(¹³C NMR)、 红外光谱(IR)及元素分析等表征, 确认了化学结构. 以甲基铝氧烷(MAO)为助催化剂, 化合物4~7为催化剂催化丙烯聚合, 考察了聚合温度、 乙烯压力、 铝钛或铝锆比对催化剂活性及聚合物分子量的影响. 结果表明, 多亚甲基桥连双核茂金属是高活性乙烯和丙烯聚合催化剂, 乙烯聚合活性最高达到7.5× 10⁶ g PE/(mol Zr·h)(化合物6), 丙烯聚合活性达 10 × 10⁵ g sPP/(mol Zr·h)(化合物4). 所得间规聚丙烯(sPP)的间规度指数(SI, r) 达到90%. 在同样条件下, 双核化合物的催化活性、 聚合物分子量M_w(> 100000)以及分子量分布(MWD>2.5)均比相应的单核化合物高(M_w<70000, MWD≤2), 表明该体系中存在较强的核效应.     

1-二茂铁基-3-[(9-乙基)咔唑-3-基]丙烯酮的合成及三阶非线性光学性质

合成了一个新的非线性光学(NLO)有机材料1-二茂铁基-3-[(9-乙基)咔唑-3-基]丙烯酮(FCAK),并通过NMR、IR、MS和元素分析等技术手段进行了表征。 采用粉末Nd∶YAG激光技术测定了标题化合物的三阶非线性光学性质并确定了相关参数。 激光脉冲为4 ns时,非线性折射率n₂=-3.5×10^-18 m²/W,非线性吸收系数β=-2.7×10^-11 m/W,三阶非线性极化率χ⁽³⁾=2.04×10^-12 esu,三阶非线性分子超极化率γ=1.1×10^-30 esu。 激光脉冲为21 ps时,n₂=0.55×10^-18 m²/W,β=-0.6×10^-11 m/W,χ⁽³⁾=3.4×10^-13 esu,γ=0.13×10^-30 esu。     

分散固相萃取-超高效液相色谱-串联质谱法测定农产品中乙拌磷及其代谢物

基于超高效液相色谱-串联质谱(UHPLC-MS/MS)建立定量分析乙拌磷及其5个代谢物(乙拌磷砜、乙拌磷亚砜、内吸磷-S、内吸磷-S-砜、内吸磷-S-亚砜)的方法,应用该方法分析其在农产品(豌豆、芦笋、小麦、咖啡豆和花生)中的残留量。对样品前处理及色谱条件进行优化,样品经过乙腈涡旋提取(小麦、咖啡豆和花生先加水润湿),经盐析分层,取上清液经50 mg C₁₈、50 mg PSA和50 mg NH₂混合分散固相萃取净化后,经Thermo Syncronis C₁₈色谱柱(150 mm×2.1 mm, 5 μm)分离,柱温40 ℃,进样量2 μL,以水和乙腈为流动相梯度洗脱后,采用ESI源,在正离子扫描和多反应监测(MRM)模式下检测,外标法定量。结果表明,乙拌磷及其代谢物在2.0~200.0 μg/L范围内线性关系良好,相关系数(R²)≥0.9981。方法的检出限(LOD)为0.02~2.0 μg/kg,并以最小添加水平5 μg/kg为定量限(LOQ)。乙拌磷及其代谢物在豌豆、芦笋、小麦、咖啡豆和花生中5、100、1000 μg/kg 3个添加水平下的平均回收率为75.0%~110.0%,相对标准偏差(RSD)为0.7%~14.9%,方法的准确度和精密度符合农药残留测定。应用建立的方法对市售的40份小麦样品和40份花生样品进行检测,均低于方法的检出限。该方法具有操作简单、快速、灵敏、准确的特点,适用于谷物、油料、蔬菜等多种农产品中乙拌磷及其代谢物的残留检测。     

V型对称三唑并噻二唑衍生物的合成与生物活性

为构筑V型对称结构的三唑并噻二唑类衍生物, 将间苯二甲酸和5-氨基间苯二甲酸分别与3-脂肪基-1,2,4-三唑(1)缩合, 在POCl₃催化下, 合成了14个V型对称结构三唑并噻二唑稠环衍生物(2a~2g和3a~3g), 其中13个化合物为首次合成.通过红外光谱、 核磁共振波谱和高分辨质谱等对目标产物的结构进行了表征. 研究了目标产物对细胞周期分裂蛋白25B(Cdc25B)和蛋白酪氨酸磷酸酶1B(PTP1B)的抑制性能, 结果发现, 部分目标产物对Cdc25B表现出良好的抑制活性, 其中化合物3b和3f的抑制活性IC₅₀值分别为(1.34±0.39)和(0.61±0.09) μg/mL, 有望作为治疗癌症的潜在Cdc25B抑制剂; 化合物3b~3g对PTP1B均表现出良好的抑制活性, 其中化合物3b和3e的IC₅₀值分别为(0.36±0.05)和(0.97±0.08) μg/mL, 有望作为治糖尿病的潜在PTP1B抑制剂.     

Salan钛双齿配合物的Sonogashira合成后修饰反应研究

报道了一种通过钯催化Sonogashira反应对具抗癌活性的ONNO型“Salan”、“2,6-吡啶二甲酸”双配位钛化合物进行高效后修饰的方法学研究. 通过Sonogashira反应直接向两个配体引入不同炔烃功能基团, 共制备了20个新型的钛配合物. 进一步通过该方法学向钛配合物引入三苯乙炔基及癌细胞靶向分子雌炔醇. 通过¹H NMR和¹³C NMR、HRMS、UV-vis和IR等手段对所有配合物进行了结构表征. 多数炔基活化的钛配合物对HeLa S3和Hep G2癌细胞在微摩尔范围内表现出显著提升的抑制活性, 其中配合物3j [Salan^2,4-dimethylTi^(IV)Dipic^{4-(3-(dimethylamino)prop-1-yn-1-yl)}]的IC₅₀值较顺铂提升约一个数量级, 是本研究中活性最强的Salan钛双齿配合物[3j, HeLa S3: IC₅₀=(0.5±0.1) μmol/L, Hep G2: IC₅₀=(0.7±0.2) μmol/L; 顺铂, HeLa S3: IC₅₀=(3.3±0.2) μmol/L, Hep G2: IC₅₀=(6.0±1.1) μmol/L]. 针对芳炔和脂肪炔取代不同配体的代表配合物2a、2f、3a和3j开展的稳定性研究表明, 向2位无取代Salan引入的炔基可通过电负性改变配合物的水稳定性, 2a和2f水解出无抗癌活性的炔基Salan配体1a*, 半数水解时间(t_1/2)分别为5和10 h. 炔基功能化2,6-吡啶二甲酸的配合物3a和3j含有2位甲基取代的Salan配体, 它们在水环境中保持稳定. 此外, 本文总结和阐释了这类新型炔基功能化钛配合物的“结构-活性”关系, 并对后续开发此类钛配合物的前景和策略做出了分析与展望.     

Highly-efficient photosensitizer based on AIEgen-decorated porphyrin for protein photocleaving

An AIEgen decorated porphyrin (TPETPyP) with ¹O₂ quantun yield as high as 0.85 in PBS was facilely prepared through a simple one-step reaction for efficient photocleavage of proteins in PDT.     

Photodynamic Therapy with a Diode Laser for Implanted Fibrosarcoma in Mice Employing Mono-L-Aspartyl Chlorin E6

Abstract— The authors performed photodynamic therapy (PDT), avoiding any hyperthermic effects, using a newly developed diode laser and photosensitizer, mono-L-aspar-tyl chlorin e₆ (NPe6), of Meth-A fibrosarcoma implanted in mice and achieved tumor therapeutic benefit. The photodynamic light treatment was performed 5 h following the photosensitizer administration. With 5.0 mg/kg NPe6 and light doses of 50, 100, 150 and 200 J/cm², the tumor cure rates were 20, 50, 70 and 90%, respectively. With 100 J/cm² laser exposure and NPe6 doses of 1.25, 2.5, 5.0, 7.5 and 10.0 mg/kg, the tumor cure rates were 0, 20, 50, 70 and 90%, respectively. A charge-coupled device (CCD) camera system was employed to measure the NPe6 fluorescence intensity correlating with the residual amount of the photosensitizer at deferent depth from the tumor surface. The ratios of the NPe6 fluorescence intensity at 3 mm from the tumor surface following 50, 100, 150 and 200 J/cm² laser exposure to no laser exposure were 0.73, 0.36, 0.22 and 0.16, respectively. With samples sectioned at 1 mm depth, after 50 J/cm² and the same photosensitizer dose (5 mg/kg) this ratio was 0.19. These results suggest that a certain increase in the tumor tissue level of NPe6 and a certain increase of laser light dose reaching deeper layers of tumor caused an increase in percent cure. In addition, the effectiveness of PDT depends on the total laser dose reaching deeper layers of tumors. Furthermore, the effectiveness of PDT tends to correlate with the amount of NPe6 photobleaching by PDT.     

Semiconducting polymer dots with photosensitizer loading and peptide modification for enhanced cell penetration and photodynamic effect

We utilized semiconducting polymer do-PFDTBT, photosensitizer ZnPc and functional polymer PSMA to prepare carboxyl Pdots. The carboxyl Pdots were modified with cell penetrating peptides (R8) to prepare peptide coated-Pdots, which could enhance the cell penetration and photodynamic effect.     

Mitochondrion-anchoring AIEgen with Large Stokes Shift for Imaging-guided Photodynamic Therapy

Photosensitizers that can target and accumulate in mitochondria are expected to achieve good therapeutic effects in photodynamic therapy,as mitochondria are the energy generation factory in cells.Herein,we designed and synthesized a novel mitochondrion-targeting photosensitizer TPC-Py with aggregation-induced emission characteristics for image-guided photodynamic therapy.TPC-Py possessed an efficient production of 1O2,with a quantum yield of 11.65%,upon mild white light irradiation(6 mW/cm²).TPC-Py exhibited good biocompatibility under dark condition,but showed remarkable cytotoxicity towards human cervical carcinoma(HeLa)cells with a half maximal inhibitory concentration(IC50)of 3.2μmol/L when exposed to white light irradiation(14.4 J/cm²).In addition,the Stokes shift of TPC-Py was as high as 150 nm,so that it could prevent self-absorption and increase the signal-to-noise ratio of fluorescence imaging.The excellent performance of TPC-Py makes it a promising candidate in imaging-guided clinical PDT for cancer in the near future.     

Electric magnetic resonance and spectrophotometry evidence on the photodynamic activity of a new perylenequinonoid pigment

Di-cysteine substituted hypocrellin B (DCHB) is a new water-soluble photosensitizer with significantly enhanced red absorption at wavelengths longer than 600 nm over the parent compound hypocrellin B (HB). The photosensitizing properties (Type I and/or Type II mechanisms) of DCHB have been investigated in dimethylsulfoxide (DMSO) and aqueous solution (pH 7.4) using electron paramagnetic resonance (EPR) and spectrophotometric methods. In anaerobic DMSO solution, the semiquinone anion radical of DCHB (DCHB^•−) is predominantly photoproduced via self-electron transfer between excited- and ground-state DCHB species. The presence of an electron donor significantly promotes the formation of the reduced form of DCHB. When a deoxygenated aqueous solution of DCHB and an electron donor are irradiated with 532 nm light, the hydroquinone of DCHB (DCHBH₂) is formed via the disproportionation of the first-formed DCHB^•− and second electron transfer to DCHB^•− from the electron donor. When oxygen is present, singlet oxygen (¹O₂), superoxide anion radical (O₂^•−) and hydroxyl radical (^•OH) are produced. The quantum yield of ¹O₂ generation by DCHB photosensitization is estimated to be 0.54 using Rose Bengal as a reference, a little lower than that of HB (0.76). The superoxide anion radical is also significantly enhanced by the presence of electron donors. Moreover, (O₂^•−) upon disproportionation generated H₂O₂ and ultimately the highly reactive ^•OH via the Haber-Weiss reaction pathway. The efficiency of (O₂^•−) generation by DCHB is obviously enhanced over that of HB. These findings suggest that the photodynamic actions of DCHB may proceed via Type I and Type II mechanisms and that this new photosensitizer retains photosensitizing activity after photodynamic therapy-oriented chemical modification.     

THE USE OF INTERNALIZABLE DERIVATIVES OF CHLORIN E6 FOR INCREASING ITS PHOTOSENSITIZING ACTIVITY

Experiments with human hepatoma PLC/PRF/5 cells and human embryo skin fibroblasts involving the use of three different tests (colony formation, Trypan blue exclusion, labeled thymidine incorporation) have demonstrated a significantly higher photosensitizing activity of chlorin e₆ conjugates with internalizable ligands as compared to that of chlorin e₆ itself. Receptor-mediated internalization of chlorin e₆ conjugates ensures a greater photosensitization of cells than binding of those conjugates to cell surface receptors. The suitability of such conjugates that permit the delivery of a photosensitizer to sensitive intracellular targets is discussed.     

A convenient synthesis of Fe(CO)2(η-S2CNMe2)2 and Fe(η-S2CNMe2)2 from the monodentate dithiocarbamato derivative, [(η-C5H5)(CO)3W(η-SCSNMe2)] and Fe2(CO)9

A high yield synthesis of the carbonyl dithiocarbamato derivative Fe(CO)₂(η²-S₂CNMe₂)₂ and Fe(η²-S₂CNMe₂)₂ by photolysis with visible light of solutions containing Fe₂(CO)₉ or Fe₃(CO)₁₂ and [(η⁵-C₅H₅)(CO)₃W(η¹-SCSNMe₂)] is reported.     

Matrix isolation infrared spectroscopic and theoretical study of noble gas coordinated dipalladium–dioxygen complexes

The reaction products of palladium atoms with molecular oxygen in solid argon have been investigated using matrix isolation infrared absorption spectroscopy and quantum chemical calculations. In addition to the previously reported mononuclear palladium–dioxygen complexes: Pd(η²–O₂) and Pd(η²–O₂)₂, dinuclear palladium–dioxygen complexes: Pd₂(η²–O₂) and Pd₂(η²–O₂)₂ were formed under visible light irradiation and were identified on the basis of isotopic substitution and theoretical calculations. In addition, experiments doped with xenon in argon coupled with theoretical calculations suggest that the Pd(η²–O₂), Pd₂(η²–O₂) and Pd₂(η²–O₂)₂ complexes are coordinated by two argon or xenon atoms in solid argon matrix, and therefore, should be regarded as the Pd(η²–O₂)(Ng)₂, Pd₂(η²–O₂)(Ng)₂ and Pd₂(η²–O₂)₂(Ng)₂ (NgAr or Xe) complexes isolated in solid argon.     

Pharmacokinetics of Tetra (m-hydroxyphenyl)chlorin in Human Plasma and Individualized Light Dosimetry in Photodynamic Therapy

The pharmacokinetics of the photosensitizer 5,10,15,20-tetra( m -hydroxyphenyl) chlorin(mTHPC) was investigated in the plasma of 20 patients by absorption and fluorescence spectroscopy. The temporal behavior was characterized by a rapid decrease in concentration during the first minutes after intravenous injection of 0.15 mg/kg mTHPC. A minimum concentration in the plasma was reached after about 45 min. The drug concentration then increased again, attaining a maximum after about 10 h, after which it decreased again with a halflife of about 30 h. Irradiation tests in the oral cavity at different time intervals after the injection revealed that the tissue re-action was only partially correlated with the mTHPC plasma level. The tissue response was stronger at later drug-light intervals (1–4 days) than during the first hours after injection even though the mTHPC plasma concentration was higher at the shorter times. Relative mTHPC concentrations were also measured in the mucosae of the oral cavity, the esophagus and the bronchi of 27 patients by light-induced fluorescence spectroscopy using an optical fiber-based spectrometer. These measurements were performed prior to photodynamic therapy (PDT), 4 days after injection of the photosensitizer. Highly significant linear correlations were found between the relative mTHPC concentrations in the mucosae of these three organs. Likewise, the plasma levels of mTHPC measured just before PDT were significantly correlated with the mTHPC concentrations in the three types of mucosae mentioned above. These results indicate that mTHPC plasma levels measured just before PDT can be used for PDT light dosimetry.     

Iron carbonyl complexes from 2-[2,3-diaza-4-(2-thienyl)buta-1,3-dienyl]thiophene: N---N bond cleavage and cyclometalation

When thienyl Schiff base 1, derived from 2-formylthiophene and hydrazine, reacted with Fe₂(CO)₉ in n-hexane, three major complexes were obtained: (1) a diironhexacarbonyl complex with two 2-thienylmethylideneamido bridging ligands 2, which resulted from the =N---N= bond cleavage of ligand 1; (2) a doubly cyclometalated di-μ-di-(η¹:η²-thienyl; η¹:η¹(N))bis(hexacarbonyldiiron) complex (3); and (3) a cyclometalated (μ-η¹:η²-thienyl; η¹:η¹(N))hexacarbonyldiiron complex (4). Molecular structures of compounds 1a, 1c, and 2a have been determined by single-crystal X-ray diffraction.