A Versatile Solid-Phase Approach to the Synthesis of Oligonucleotide Conjugates with Biodegradable Hydrazone Linker

One of the ways to efficiently deliver various drugs, including therapeutic nucleic acids, into the cells is conjugating them with different transport ligands via labile or stable bonds. A convenient solid-phase approach for the synthesis of 5′-conjugates of oligonucleotides with biodegradable pH-sensitive hydrazone covalent bonds is proposed in this article. The approach relies on introducing a hydrazide of the ligand under aqueous/organic media to a fully protected support-bound oligonucleotide containing aldehyde function at the 5′-end. We demonstrated the proof-of-principle of this approach by synthesizing 5′-lipophilic (e.g., cholesterol and α-tocopherol) conjugates of modified siRNA and non-coding RNAs imported into mitochondria (antireplicative RNAs and guide RNAs for Mito-CRISPR/system). The developed method has the potential to be extended for the synthesis of pH-sensitive conjugates of oligonucleotides of different types (ribo-, deoxyribo-, 2′-O-methylribo-, and others) with ligands of different nature.     

N-（p-羟基苯基）甲基丙烯酰胺的合成与表征

N-芳基取代的甲基丙烯酰胺(结构式如图1所示)是一类非常有用的共聚单体,它们可以与甲基丙烯酸酯或N-取代马来酰亚胺等单体共聚,使共聚物的一些性能,如耐热性、耐水性、透明度、硬度等都有不同程度的改进[1-4].关于N-芳基取代的甲基丙烯酰胺的制备,文献[5-8]曾有报道,通常采用甲基丙烯酰氯与芳基胺在乙醚、苯等溶剂中反应,并加入适当的缚酸剂来完成.而N-(p-羟基苯基)甲基丙烯酰胺(此处R＝OH)是N-芳基取代甲基丙烯酰胺中一种比较特殊的单体,它即含有碳碳双键,又含有酚羟基,属于双官能团物质.关于它的制备及用途,尚未见有文献报道.文献[5]曾报道说,采用对胺基苯酚与甲基丙烯酰氯反应仅能得到甲基丙烯酸(N-(p-甲基丙烯酰胺基)苯酚酯(即酰胺-酯化合物).本文合成出了这种物质,并对其进行了表征和证实;我们推测它与一些单体(如N-取代马来酰亚胺等)的共聚物可以溶于碱性水溶液,并且有好的耐热性,因此在紫外光刻胶中可能有比较大的应用潜力[9-11],有关这方面的内容我们将另文报道.     

N－（4－烯丙氧基苯基）马来酰亚胺的合成

Ｎ－取代马来酰亚胺与双马来酰亚胺的混合物可制备耐热性高、工艺性好的热固性高分子材料。本文通过对氨基酚与乙酸肝的反应，再通过酚羟基的醚化反应和乙酰氨基的水解反应，并与顺丁烯二酸酐进行酰亚胺化成环反应，合成并鉴定了标题化合物。     

Unusual course of the reaction of N-(tosylmethyl)thiourea and N-(azidomethyl)thiourea with sodium enolate of dimedone

The end product of the reaction of N-(tosylmethyl)thiourea or N-(azidomethyl)thiourea with sodium enolate of dimedone is bis(2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-enyl)methane (methylenebisdimedone) instead of the expected 8a-hydroxy-7,7-dimethyl-2-thioxoperhydroquinazolin-5-one.M. V. Lomonosov State Academy of Fine Chemical Technology, Moscow 117571, Russia; Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 70–72, January, 2000.     

N─苯基邻苯二甲酰亚胺和N─对甲苯基邻苯二甲酰亚胺的晶体和分子结构

报道一种新类型的有机电子晶体Ｎ－苯基邻苯二甲酰亚胺（１）（Ｃ＿（１４）Ｈ＿９ＮＯ＿２）和Ｎ－对甲苯基邻苯二甲酰亚胺（２）（Ｃ＿（１５）Ｈ＿（１１）ＮＯ＿２）的晶体和分子结构，（１）属正交晶系，空间群为Ｐｃａｂ，ａ＝７．６４９（４），ｂ＝１１．６５９（２），ｃ＝２３．７３９（３）Ａ，Ｖ＝２１１７．０Ａ￣３，Ｚ＝８，Ｄ＿ｃ＝１．４０１ｇ／ｃｍ￣３，Ｍ＿ｒ＝２２３．２３，μ＝０．８８５ｃｍ￣（－１），最终偏离因子Ｒ＝０．０５３，Ｒ＿ω＝０．０４８；（２）属正交晶系，空间群为Ｐｎａ２＿１，ａ＝７．６２４（２），ｂ＝１１．２３７（１），ｃ＝１３．８５６（２）Ａ，Ｖ＝１１８７．０　Ａ３，Ｚ＝４，Ｄ＿ｃ＝１．３２８ｇ／ｃｍ￣３，Ｍｒ＝２３７．２６，μ＝２．７６４ｃｍ－１，最终偏离因子Ｒ＝０．０３６，Ｒ＿ω＝０．０３２。晶体结构测定结果表明，邻苯二甲酰亚胺的内酰亚胺碳、氮、氧原子与其苯并环共平面。化合物（２）中的甲基碳原子与取代基苯环共平面，苯并酰亚胺平面与取代苯环平面间的夹角分别为５８．４°（化合物１）和５６．２°（化合物２）。     

N─苯基邻苯二甲酰亚胺和N─对甲苯基邻苯二甲酰亚胺的晶体和分子结构

报道一种新类型的有机电子晶体Ｎ－苯基邻苯二甲酰亚胺（１）（Ｃ＿（１４）Ｈ＿９ＮＯ＿２）和Ｎ－对甲苯基邻苯二甲酰亚胺（２）（Ｃ＿（１５）Ｈ＿（１１）ＮＯ＿２）的晶体和分子结构，（１）属正交晶系，空间群为Ｐｃａｂ，ａ＝７．６４９（４），ｂ＝１１．６５９（２），ｃ＝２３．７３９（３）Ａ，Ｖ＝２１１７．０Ａ￣３，Ｚ＝８，Ｄ＿ｃ＝１．４０１ｇ／ｃｍ￣３，Ｍ＿ｒ＝２２３．２３，μ＝０．８８５ｃｍ￣（－１），最终偏离因子Ｒ＝０．０５３，Ｒ＿ω＝０．０４８；（２）属正交晶系，空间群为Ｐｎａ２＿１，ａ＝７．６２４（２），ｂ＝１１．２３７（１），ｃ＝１３．８５６（２）Ａ，Ｖ＝１１８７．０　Ａ３，Ｚ＝４，Ｄ＿ｃ＝１．３２８ｇ／ｃｍ￣３，Ｍｒ＝２３７．２６，μ＝２．７６４ｃｍ－１，最终偏离因子Ｒ＝０．０３６，Ｒ＿ω＝０．０３２。晶体结构测定结果表明，邻苯二甲酰亚胺的内酰亚胺碳、氮、氧原子与其苯并环共平面。化合物（２）中的甲基碳原子与取代基苯环共平面，苯并酰亚胺平面与取代苯环平面间的夹角分别为５８．４°（化合物１）和５６．２°（化合物２）。     

Asymmetric Synthesis of N-（Diphenylphosphinyl）furfurylamine by the Enantioselective Alkylation of Furfurylimine

Optically active N-（diphenylphosphinyl）furfurylamines 2 with good ee values were obtained by the enantioselective addition of dialkylzincs to furfuryl imine 1 in the presence of chiral aminoalcohol derivatives and oxazolines.     

N-(P-羟甲基苯基)咔唑丙烯酸酯的合成和聚合

<正> 为了深入认识含咔唑基单体的光敏性与聚合性的关系,在本系列含咔唑基化合物的基础上,合成了两个新单体:N-(p-羟甲基苯基)咔唑丙烯酸酯和N-(P-羟甲基苯基)咔唑甲基丙烯酸酯,并研究了其聚合行为。 化合物Ⅰ、Ⅱ、Ⅲ和聚合物的合成,反应式如下:     

Improved Methodology for the Synthesis of a Cathepsin B Cleavable Dipeptide Linker,Widely Used in Antibody-Drug Conjugate Research

Antibody-drug conjugates (ADCs) represent an emerging class of biopharmaceutical agents that deliver highly potent anticancer agents (payloads) selectively to tumors or components associated with the tumor microenvironment. The linker, responsible for the connection between the antibody and payload, is a crucial component of ADCs. In certain examples the linker is composed of a cleavable short peptide which imparts an additional aspect of selectivity. Especially prevalent is the cathepsin B cleavable Mc-Val-Cit-PABOH linker utilized in many pre-clinical ADC candidates, as well as the FDA approved ADC ADCETRIS^® (brentuximab vedotin). An alternative route for the synthesis of the cathepsin B cleavable Mc-Val-Cit-PABOH linker is reported herein that involved six steps from l-Citrulline and proceeded with a 50% overall yield. In this modified route, the spacer (a para-aminobenzyl alcohol moiety) was incorporated via HATU coupling followed by dipeptide formation. Importantly, this route avoided undesirable epimerization and proceeded with improved overall yield. Utilizing this methodology, a drug-linker construct incorporating a potent small-molecule inhibitor of tubulin polymerization (referred to as KGP05), was synthesized as a representative example.     

Synthesis and Crystal Structure of N-(5-Phenylseleno)pentyl Succinimide

N-(5-phenylseleno)pentyl succinimide 1, C15H19NO2Se Mr = 324.27, was prepared by treating BrCH25SePh with potassium succinimide. Its crystal structure has been determined by X-ray single-crystal diffraction. The crystal of 1 belongs to monoclinic system, space group P21/c with the crystal cell parameters: a = 18.018(6), b = 5.980(2), c = 14.682(5)A, β = 109.977(6)°, V = 1486.7(9)A3, Z = 4, Dc = 1.449 g/cm3, μMoKα = 2.523 mm-1, F(000) = 664,the final R = 0.0302 and wR = 0.0666 for 2623 independent observed reflections with I>2σ(I). Structure analyses revealed that there exist strong nonclassical hydrogen bonds C-H…O.     

Synthesis and Characterization of N-(O,O-Dialkyl Phosphoryl)-D-glucosamine

Using D-glucosamine hydrochloride as a starting material and alkylphosphite as the phosphorylating agent, a new analogue of glycosyl phosphate, namely N-(O, O-dialkyl phosphoryl)-D-glucosamine, was synthesized without hydroxyl protection by Atherton–Todd reaction. The structure of N-(O, O-dialkyl phosphoryl)-D-glucosamine was determined by FT-IR, ¹H NMR, ¹³C NMR, ³¹P NMR, and HR MS. This concise and convenient synthetic pathway provides a new approach for the preparation of N-phosphoryl glucosamine derivatives.

Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.     

Polystyrene bis[N-(2-pyridyl) sulfonamide] palladium(II): Synthesis,characterization as a catalyst for coupling reactions

The [N-(2-pyridyl)] para-styrene sulfonamide (PSS) was prepared as a monomer, from the reaction of para-styrene sulfonyl chloride and 2-amino pyridine in the presence of potassium hydroxide solution 0.5 M as a base, and CH₃Cl. Polystyrene [N-(2-pyridyl) sulfonamide] (PPSS) was synthesized from the polymerization of [N-(2-pyridyl)] para-styrene sulfonamide (PSS). The Polystyrene bis [N-(2-pyridyl) sulfonamide] palladium (II) as a polymer- supporting palladium complex was also prepared from the reaction of PdCl₂ (CH₃CN)₂ with PPSS in the presence of KOH 0.5 M. Polystyrene bis [N-(2-pyridyl) sulfonamide] palladium (II) is produced as a novel heterogeneous catalyst for coupling reactions for C-C bond formation. This method includes higher yield and has an easier work-up procedure. The structures of the monomer, polymer and its Pd complex were confirmed by using FT-IR and ¹H-NMR spectroscopy. Elemental analysis of Pd by inductively coupled plasma (ICP) technique and hot filtration test showed loading of the metal into solution from the catalyst The heterogeneous catalyst was recycled without any loss in its properties.     

Palladium(II) Complexes of N-(2-Thienylmethylidene)aniline Derivatives

Coordination reactions of N-(2-thienylmethylidene)aniline derivatives, L, with PdCl₂ or [PdCl₄]^2? in ethanol yield stable complexes of the type trans-(L)₂PdCl₂ with the azomethine nitrogen atoms as σ donors. These are not readily convertible to othor-palladated complexes. An X-ray crystallographic study of the complex (L₂)₂PdCl₂ reveals a centrosymmetric geometry. The structure is in the triclinic space group $ {\rm P}\bar 1 $ with a = 8.633(2) Å, b = 12.759(3) Å, c = 8.398(2) Å, α = 96.65(5)°, β = 111.47(5)*, γ= 101.28(6)°, and Z = 1. The final R factor is 0.043 (Rw = 0.044) for 2396 observed reflections. There is no real bonding between a thiophene sulfur atom and a central palladium ion. However, a long distance interaction between S and Pd does exist.     

N-(2-氨基苯基)-2-喹唑啉酮乙酰胺盐酸盐的合成

本文通过2-溴-N-(2-硝基苯)乙酰胺和取代的喹唑啉酮在NaH催化下发生亲核取代反应,再经过氢化、酸化合成了4个新型常山碱类抗球虫药物-N-(2-氨基苯基)-2-喹唑啉酮乙酰胺盐酸盐(1∶1)。其中,2-溴-N-(2-硝基苯)乙酰胺通过溴乙酰氯与邻硝基苯胺反应制备,取代的喹唑啉酮使用取代的邻氨基苯甲酸与甲酰胺反应合成。所有目标化合物的结构均经1H NMR,IR和HRMS等方法确证。     

Synthesis and Crystal Structure of a Copper(II) Compound Constructed by N-(4,6- Dimethoxylpyrimidin)-N'-(ethoxycarbonyl)thiourea

A copper(Ⅱ) complex Cu(L)2(NO3)2 constructed by the L (L = N-(4,6-dime- thoxylpyrimidin)-N'-(ethoxycarbonyl)thiourea) ligand crystallizes in monoclinic, space group C2/c with a = 16.2416(16), b = 9.1385(7), c = 22.0008(18) (A),β = 108.077(2)°, V ＝ 3104.3(5)(A)3, Dc = 1.627 g/cm3, Z = 4, C20H28CuN10O14S2, Mr = 760.18, μ(MoKα) = 0.920 mm-1, F(000) = 1564, R = 0.0471 and wR = 0.1284 for 2239 observed reflections (I > 2σ(I)). X-ray diffraction shows the existence of weak complementary intramolecular N-H…O (DA) hydrogen bonds which further strengthen the coordination from the two L ligands with the Cu(II) ion, intermolecular C-H…O hydrogen bonds and weak π…π stacking interactions, leading to the formation of a multi-dimen- sional supramolecular network.     

5-溴水杨醛缩乙醇胺Schiff碱Cu(II)配合物的合成和晶体结构

The title complex Cu(L)₂ [HL=N-(5-bromosalicylidene)-2-aminoethanol] was synthesized by the reaction of Cu(CH₃COO)₂·H₂O with N-(5-bromosalicylidene)-2-aminoethanol in the ethanol. It was characterized by elemental analysis, IR and X-ray single crystal diffraction analysis. The crystal of the title complex [Cu(C₉H₉BrNO₂)₂] belongs to monoclinic, space group P2₁/n with a=1.319 1(5) nm, b=0.444 58(16) nm, c=1.656 7(6) nm, β=91.226(5)°, V=0.971 46(6) nm³, Z=2, D_c=1.879 Mg·m^-3, μ=5.264 mm^-1, F(000)=542, and final R₁=0.045 6, wR₂=0.097 0. The complex comprises a four-coordinated copper(II) center, with an N₂O₂ planar coordination environment. The molecules are connected by hydrogen bonds to form two-dimensional layered structure. CCDC: 274180.     

Synthesis and Crystal Structure of N-(Biphenyl-2-thiocarbamoyl)-4-(1,3-dichlorophenyl) Carboxamide

The synthesis of the title molecule was achieved by the reaction of 2,4-dichlorobenzoyl chloride with potassium thiocyanate in 1:1 molar ratio in dry acetonitrile to afford the corresponding isothiocyante in situ followed by the treatment with 2-aminobiphenyl. The structure of the target compound was established by elemental analysis, FTIR, 1H, 13 C NMR and mass spectroscopy and unequivocally confirmed by the crystallographic data. The title compound crystallizes in the monoclinic space group P21/n with a = 13.356(2), b = 7.0761(11), c = 20.539(3) , β = 105.723(4)°, V = 1868.5(5) 3 and Z = 4.     

基于紫外光谱的N-2,4-二硝基苯基吡啶季铵盐的开环

吡啶季铵盐的开环是有机合成中的一个重要的多步串联反应,应用领域广阔。 但目前对其开环机理尚存一些争议。 基于开环前后,其分子共轭结构的差异,利用紫外光谱对吡啶季铵盐的开环反应过程进行了研究,并对形成其关键中间体1-苯胺基-5-苯亚胺基-1,3-戊二烯的影响因素进行了优化。 此外,将超声辐射引入吡啶季铵盐的开环过程,提升了开环的效率,开环速率提高了94%。     

N-(p-乙烯氧基苯基)咔唑的合成和聚合

本文是含咔唑化合物及其聚合物系列研究的一部分,以对-溴苯酚为原料,经过乙烯基醚化,再同咔唑反应、合成了新的单体,N-(p-乙烯氧基苯基)咔唑(NEOPC),经过元素分析、NMR和IR等对NEOPC进行分析鉴定,研究了它的聚合行为。     

Complexes of cobalt(2+) chloride with hydrochlorides of N-(1,2,4-triazol-5-yl)- and N-(tetrazol-5-yl)benzamidines

We have synthesized complex compounds of Co(2+) chloride with hydrochlorides of N-(1,2,4-triazol-5-yl)benzamidine and N-(tetrazol-5-yl)benzamidine. According to magnetochemistry and electron spectroscopy data, the ligands are coordinated in a bidentate fashion with the N atom of the amidine group and the N atom of the heterocycle with formation of the tetrahedral chromophore CoN₂Cl₂.Institute of Inorganic Chemistry, Siberian Branch, Russian Academy of Sciences, 630090 Novosibirsk. N. D. Zelinskii Institute of Organic Chemistry, Russian Academy of Sciences, 117913 Moscow. Translated from Izvestiya Akademii Nauk, Seriya Khimicheskaya, No. 10, pp. 2311–2315, October, 1992.