含丝氨酸和组氨酸残基手性肽核酸单体的合成

设计合成了含组氨酸残基碱基为胸腺嘧啶的手性肽核酸单体, 咪唑氨基的最终保护基为2,4-二硝基苯基(Dnp). 对文献合成方法进行了适当改进, 制备了两种含丝氨酸和组氨酸残基碱基为腺嘌呤的手性肽核酸单体, 以上化合物均可作为制备手性肽核酸的基本构建单元.     

手性膦肽核酸单体的合成

肽核酸是一种潜在的反义和反基因药物。膦肽结构的引入克服了肽核酸低水溶性和低细胞膜通透性等缺点,有利于肽核酸的应用。本研究报道手性磷肽核酸单体的合成。还原氨化方法被用于实现N-Boc,N-Fmoc保护的丙氨醛与甘氨膦酸二酯的偶联,BBC-Cl,FEP等缩合剂被用于实现碱基侧链和母链的高效缩合。     

肽核酸的合成、修饰和应用

肽核酸是寡核苷酸模拟物, 它的糖-磷酸骨架被N-(2-氨基乙基)甘氨酸骨架所代替. 为了优化肽核酸的性质, 各种结构的肽核酸(PNA)单体被合成出来. 综述了肽核酸的合成、结构修饰及应用.     

手性酰胺聚硅氧烷固定相的制备与气相色谱性能

以L-苯丙氨酸,L-缬氨酸为手性源,合成了二种含末端烯基,具有刚性苯基链节的新型手性酰胺单体;并通过硅氢加成方法将其接枝到含氢硅油上,制备了两种新型手性酰胺聚硅氧烷固定相.这一新方法具有简单易行,各步产率较高的优点,所制备的手性固定相具有较好的毛细管柱色谱性能.手性拆分能力和耐温性.     

手性酰胺聚硅氧固定相的制备与气相色谱性能

以Ｌ－苯丙氨酸，Ｌ－缬氨酸为手性源，合成了二种含末端烯基，具有刚性苯基链节的新型手性酰胺单体；并通过硅氢加成方法将其接枝到含氢硅油上，制备了两种新型手性酰胺聚硅氧烷固定相。这一新方法具有简单易行，各步产率较高的优点，所制备了手性固定相具有较好的毛细管柱色谱性能。手性拆分能力和耐温性。     

基于L-异亮氨酸衍生物的液晶单体及其聚合物的合成与结构表征

通过对L-异亮氨酸化合物进行扩展性研究及分子设计,本论文合成了四种含(2S,3S)-3-甲基-2-氯戊酰氧基的手性液晶单体(M1～M4),然后再以六氯合铂酸为引发剂,将四种单体通过接枝聚合,获得了对应的聚硅氧烷类液晶高分子(P1～P4),采用FT-IR、1 H-NMR与GPC表征了所合成的中间体、手性液晶单体及其聚合物的化学结构与分子量及分布,结果符合分子设计.此外,采用旋光仪测定了手性单体的旋光度,研究表明:它们均为右旋化合物,其比旋光度随化合物刚性的增加而降低,而对于端基相同、液晶核刚性大小接近的单体,其比旋光度比较接近.     

乙烯基二联苯单体的螺旋选择性自由基聚合

为了深入理解乙烯基二联苯单体自由基聚合过程中的手性传递,进行了手性单体(+)-2-[(S)-异丁氧羰基-5-(4′-己氧基苯基)苯乙烯、非手性单体2-丁氧羰基-5-(4′-己氧基苯基)苯乙烯的均聚反应及它们二者的共聚反应,探讨了聚合温度和溶剂性质对手性单体均聚物旋光活性、手性单体含量对共聚物旋光活性以及聚合反应溶剂的超分子手性对共聚物旋光活性的影响.研究发现,降低聚合温度、采用液晶性反应介质有利于得到旋光度大的聚合物;少量手性单体的引入即可诱导共聚物形成某一方向占优的螺旋构象,比旋光度随手性单体的含量增加呈线性增长;在胆甾相液晶中制备的非手性单体聚合物不具有光学活性.这些结果表明,该类乙烯基二联苯聚合物具有动态螺旋构象,其光学活性主要依赖于主链的立构规整度和侧基不对称原子的手性.     

烯丙基-β-环糊精基手性毛细管电色谱整体柱的一步法制备及其性能

以烯丙基-β-环糊精、甲基丙烯酸缩水甘油酯和乙二醇二甲基丙烯酸酯为功能单体,一步键合制备了环糊精聚合物毛细管整体柱.在电色谱模式下18种氨基酸对映体得到成功分离.研究发现,将修饰的环糊精衍生物作为功能单体制备出的毛细管整体柱对疏水性,含氨基和苯环的手性化合物具有良好的保留行为,并具有良好的稳定性和重现性.新型电色谱柱也被应用于手性药物的分离.     

膦手性丙炔胺脯氨酸磷酸酯螺旋聚合物的合成与表征

通过添加对映体拆分剂,合成了4种含膦手性的丙炔胺磷酸酯单体[HC帒CC H2NH(PO)R1R2].单体1,R1=OPh,R2=NC4H7COOCH3;单体2,R1=OPh,R2=NC4H7COOCH2CH3;单体3,R1=OPh,R2=NC4H7-COOC(CH3)3;单体4,R1=Ph,R2=NC4H7COOC(CH3)3].1H-NMR和31P-NMR表征可知对映体(单体1)不能被拆分剂拆分,而单体2、单体3、单体4通过拆分剂可以制得单一手性的磷化合物.以(nbd)Rh+[η6-C6H5B--(C6H5)3]为催化剂,以三氯甲烷为溶剂成功得到聚合物分子量范围在0.4×10-4～0.7×10-4,分子量分布在1.26～1.98范围的3种含手性膦侧基的丙炔胺类聚合物.比旋光度([α]D)、圆二色谱(CD)对聚合物的不同侧基及温度对光学活性的影响表明,聚合物具有良好的光学活性且能够形成单一方向的螺旋构象,说明膦手性在构建螺旋聚合物具有重要作用.     

手性温敏凝胶Poly(NIPAM-co-AAc-L-Trp)的制备及性能

利用L-色氨酸(L-Trp)为手性源,经酯化、缩合等反应制备手性单体AAc-L-Trp,进而在交联剂N,N’-亚甲基双丙烯酰胺(MBAA)和引发剂偶氮二异丁腈(AIBN)的作用下,与N-异丙基丙烯酰胺(NIPAM)发生自由基共聚制备了一种可用于手性拆分的新型手性温敏水凝胶Poly(NIPAM-co-AAc-L-Trp),其结构经IR确证.通过对其温敏性研究发现,相比于PNIPAM凝胶,疏水性手性单体的引入使Poly(NIPAM-co-AAc-L-Trp)凝胶的温敏性下降,LCST随着手性单体含量的增加而降低.以DL-苯丙氨酸为模型药物对其手性识别和拆分性能进行研究,结果表明,手性温敏凝胶可选择性地吸附D-型对映体,且吸附量随着手性单体含量增加而增加;提高温度(45°C)有利于手性温敏凝胶对DL-苯丙氨酸的拆分.     

Coordination-driven inversion of handedness in ligand-modified PNA

Peptide nucleic acid (PNA) is a synthetic analogue of DNA, which has the same nucleobases as DNA but typically has a backbone based on aminoethyl glycine (Aeg). PNA forms duplexes by Watson Crick hybridization. The Aeg-based PNA duplexes adopt a chiral helical structure but do not have a preferred handedness because they do not contain a chiral center. An L-lysine situated at the C-end of one or both strands of a PNA duplex causes the duplex to preferably adopt a left-handed structure. We have introduced into the PNA duplexes both a C-terminal L-lysine and one or two PNA monomers that have a γ-(S)-methyl-aminoethyl glycine backbone, which is known to induce a preference for a right-handed structure. Indeed, we found that in these duplexes the γ-methyl monomer exerts the dominant chiral induction effect causing the duplexes to adopt a right-handed structure. The chiral PNA monomer had a 2,2':6',2'-terpyridine (Tpy) ligand instead of a nucleobase and PNA duplexes that contained one or two Tpys formed [Cu(Tpy)(2)](2+) complexes in the presence of Cu(2+). The CD spectroscopy studies showed that these metal-coordinated duplexes were right-handed due to the chiral induction effect exerted by the S-Tpy PNA monomer(s) except for the cases when the [Cu(Tpy)(2)](2+) complex was formed with Tpy ligands from two different PNA duplexes. In the latter case, the metal complex bridged the two PNA duplexes and the duplexes were left-handed. The results of this study show that the preferred handedness of a ligand-modified PNA can be switched as a consequence of metal coordination to the ligand. This finding could be used as a tool in the design of functional nucleic-acid based nanostructures.     

Synthesis of new chiral PNAs bearing a dipeptide-mimic monomer with two lysine-derived stereogenic centres

The synthesis of new chiral PNA analogues based on lysine is reported. In particular, l- and/or d-lysine-based PNA submonomers bearing two lysine side chains exactly spaced as in the dipeptide Lys-Lys were synthesized and incorporated in the middle of decameric PNA strands, obtaining four diastereomeric (LD, DL, LL and DD) lysine-based chiral PNAs. The hybridization with their complementary antiparallel DNA strand was studied by melting temperature determination and compared with the analogue achiral PNA and chiral PNAs bearing one residue with either of the two lysine enantiomers. The binding abilities were shown to be strongly dependent on the configuration of the stereogenic centres.     

DNA and RNA binding properties of an arginine-based ‘Extended Chiral Box’ Peptide Nucleic Acid

Lys-based ‘chiral box’ Peptide Nucleic Acids (PNAs with three adjacent 2D-Lys-based chiral monomers) have shown unsurpassed specificity in DNA recognition. In this Letter, the binding performances of arginine-based chiral PNAs were evaluated for PNAs containing in the middle part of the strand either a 2D,5L-Arg monomer or three adjacent 2D-; 2D,5L-; 5L-Arg monomers (‘Extended Chiral Box’), a combination never studied before. The binding performances of the PNAs were studied by evaluating the melting temperatures of fullmatch and mismatch PNA-DNA and PNA-RNA hybrids and by studying their structure by circular dichroism (CD). The data indicated that the arginine side chains inserted in the PNA structure are perfectly equivalent to lysine side chains as far as oligonucleotide recognition is concerned. The insertion of an ‘Extended Chiral Box’ into PNA differently influences the binding properties to DNA and RNA: the additional side chains had no observable effect on binding affinity and selectivity toward DNA, whereas, seemed to slightly disturb the binding affinity to RNA but at the same time highly enhancing the recognition selectivity.     

Synthesis of pyrrolidinone PNA: a novel conformationally restricted PNA analogue

To preorganize PNA for duplex formation, a new cyclic pyrrolidinone PNA analogue has been designed. In this analogue the aminoethylglycine backbone and the methylenecarbonyl linker are connected, introducing two chiral centers compared to PNA. The four stereoisomers of the adenine analogue were synthesized, and the hybridization properties of PNA decamers containing one analogue were measured against complementary DNA, RNA, and PNA strands. The (3S,5R) isomer was shown to have the highest affinity toward RNA, and to recognize RNA and PNA better than DNA. The (3S,5R) isomer was used to prepare a fully modified decamer which bound to rU10 with only a small decrease in Tm (delta Tm/mod = 1 degree C) relative to aminoethylglycine PNA.     

Enantiomeric separation of chiral peptide nucleic acid monomers by capillary electrophoresis with charged cyclodextrins

Direct chiral separation of chiral peptide nucleic acid (PNA) monomers has been achieved for the first time by capillary electrophoresis (CE) with charged cyclodextrins as chiral selectors added to the electrophoretic buffer. Selectively modified 6-deoxy-6-N-histamino-beta-cyclodextrin and sulfobutyl ether-beta-CD were successfully used as chiral selectors for the enantiomeric separation of chiral monomers based on different aminoethylamino acids bearing thymine or adenine as nucleobases. Chiral separations were obtained at low selector concentrations (1-3 mM) with good enantioselectivity and resolution factors. Separations were optimized as a function of pH in order to exploit the effect of the electrostatic interactions between the oppositely charged selector and selectand. The method has been applied to the analysis of the enantiomeric excess of chiral monomers used for the solid phase synthesis of chiral PNA oligomers. CE chiral analysis showed that a very high enantiomeric purity was generally achieved in the synthesis of all monomers, except for histidine and aspartic acid based monomers in which ca. 10% of the "wrong" enantiomer was always present.     

Synthesis and characterization of (R)-miniPEG-containing chiral γ-peptide nucleic acids using the Fmoc strategy

Diethylene glycol (miniPEG)-containing chiral γPNA is considered to be one of the best PNA derivatives. Its preparation is mainly based on the Boc strategy for solid phase peptide synthesis (SPPS), requiring the repeated use of trifluoroacetic acid TFA, which is not suitable for the in situ synthesis of PNA arrays and some other applications under mild conditions. Herein, Fmoc/Cbz orthogonal protected miniPEG-containing chiral γPNA monomers were synthesized, and a 15mer γPNA was prepared using the Fmoc strategy under mild conditions.     

(1S,2R/1R,2S)-cis-cyclopentyl PNAs (cpPNAs) as constrained PNA analogues: synthesis and evaluation of aeg-cpPNA chimera and stereopreferences in hybridization with DNA/RNA

Conformationally constrained chiral PNA analogues were designed on the basis of stereospecific imposition of a 1,2-cis-cyclopentyl moiety on an aminoethyl segment of aegPNA. It is known that the cyclopentane ring is a relatively flexible system in which the characteristic puckering dictates the pseudoaxial/pseudoequatorial dispositions of substituents. Hence, favorable torsional adjustments are possible to attain the necessary hybridization-competent conformations when the moiety is imposed on the conventional PNA backbone. The synthesis of the enantiomerically pure 1,2-cis-cyclopentyl PNA monomers (10a and 10b) was achieved by stereoselective enzymatic hydrolysis of a key intermediate ester 2. The chiral (1S,2R/1R,2S)-aminocyclopentylglycyl thymine monomers were incorporated into PNA oligomers at defined positions and through the entire sequence. Hybridization studies with complementary DNA and RNA sequences using UV-Tm measurements indicate that aeg-cpPNA chimera form thermally more stable complexes than aegPNA with stereochemistry-dependent selective binding of cDNA/RNA. Differential gel shift retardation was observed on hybridization of aeg-cpPNAs with complementary DNA.     

Cyclobutyl-carbonyl substituted PNA: synthesis and study of a novel PNA derivative

A new, optically active, cyclobutyl-carbonyl substituted PNA monomer has been synthesized stereoselectively from a chiral amino acid prepared from (+)-α-pinene. A conformational search shows a lack of conformational bias for the monomer and incorporation of the monomer into a standard oligomer is tolerated without changing the binding affinity towards sequence complementary RNA, DNA or PNA targets.     

Direction control in DNA binding of chiral D-lysine-based peptide nucleic acid (PNA) probed by electrospray mass spectrometry

The DNA binding abilities of peptide nucleic acids (PNAs), both achiral and bearing three adjacent D-lysine-based monomers in the middle of the strand ("chiral box" PNA), were studied by means of electrospray mass spectrometry (ESI-MS). In contrast with achiral PNA, "Chiral box" PNA was confirmed to exert high direction control (antiparallel vs. parallel DNA target) in DNA binding.