Intercalation,Cytotoxicity,and Molecular Modeling of Acenaphtho[1,2-b]pyrrole Chromophores as a New Family of Antitumor Agents

To explore new platform for DNA intercalation and potent antitumor agent, a series of 8-oxo-8H- acenaphtho[1,2-b]pyrrole-9-carboxylic acid esters chromophores has been studied. Their intercalation geometries with DNA were rex;ealed through absorption titration, SYBR Green-DNA melt curve, circular dichroism（CD）, and docking studies. It was identified that some of the compounds could intercalate into DNA along their long axis parallel to the base-pair long axis, making right-handed B form DNA transform to A-like conformation. Their binding potency varied with the different steric hindrance. Their cytotoxicity（IC50） against MCF-7 cells was found to range between 1.3 to 40.9 umol/L by MTT assay. Interestingly, the IC50 values did not show any obvious correlation to their binding constants with DNA. The chromophore with a carboxyl group exhibited the most potency of intercalating DNA and could be the promising precursor for the future intercalator for DNA, while the bromide demonstrated the highest cytotoxic activity in this series of compounds.     

Molecular modeling on the recognition of DNA sequence and conformational repair of sheared DNA by novel chiral metal complex D, L-[Co(phen)_2hpip]~(3 )

Recent studies revealed that DNA, once considered as a very stable macromolecular, is rather unstable. Familiar factors, like heavy metal, microbe, high fre-quency electromagnetic radiation and so on, could easily damage the structure of DNA in different …     

Molecular modeling on the recognition of DNA sequence and conformational repair of sheared DNA by novel chiral metal complex D,L-[Co(phen)2hpip]3+

A study on the recognition of DNA sequence and conformational repair of sheared DNA by Novel Chiral Metal complex D,L-[Co(phen)₂hpip]³⁺ (phen=1,10 phenanthroline, hpip=2-[2-hydroxyphenyl] imidazole [4,5-f][1,10] phenanthroline) is carried out with molecular simulations. The results reveal that two isomers of the complex could both recognize the normal DNA in the minor groove orientation, while recognize the sheared DNA in the major groove orientation and both isomers could convert the conformation of mismatched bases from sheared form to parallel form. Further analysis shows that the steric details of complex’s intercalation to base stack determine the results of recognition, which is induced by the steric collision among ancillary ligand phen, bases and DNA backbone, and by the steric crowding occurring in the process of structural expansion of bases and DNA backbone. Detailed analysis reveals that the conformational repair of mismatched bases relates not only to the steric interactions, but also the π-π stack among normal bases, mismatched bases and hpip ligand.     

DNA modification by cis-diaminoplatinum(ii) complexes with aminonitroxide ligands

The mixed-ligand complexes cis-Pt^II[R(CH₂)_nNH₂](NH₃)X₂, where R = 2,2,6,6-tetramethyl-1-oxylpiperidin-4-yl, X₂ = ClI or Cl₂, n = 1 or 2, and binuclear complexes trans-3,4-bis[cis-ammine(iodochloro or dichloro)platinum(ii)amino]-2,2,6,6-tetramethylpiperidin-1-oxyls were synthesized. The reactivity of the aminonitroxide complexes toward DNA, the destabilizing effect of the adducts on DNA structure, and the distribution of the Pt adducts along the DNA duplex were studied. The platination activity of the complexes is affected by the natures of both the leaving ligands X and the carrying amino ligands. The decrease in the platination activity of the complexes with an increase in the amino ligand sizes is probably caused by steric hindrance. The complexes that effectively platinate isolated DNA and cause a moderate destabilizition of DNA duplex possess high antitumor activities.     

Molecular modeling on the recognition of DNA sequence and conformational repair of sheared DNA by novel chiral metal complex D,L-[Co(phen)2hpip]3+

A study on the recognition of DNA sequence and conformational repair of sheared DNA by Novel Chiral Metal complex D,L-[Co(phen)₂hpip]³⁺ (phen=1,10 phenanthroline, hpip=2-[2-hydroxyphenyl] imidazole [4,5-f][1,10] phenanthroline) is carried out with molecular simulations. The results reveal that two isomers of the complex could both recognize the normal DNA in the minor groove orientation, while recognize the sheared DNA in the major groove orientation and both isomers could convert the conformation of mismatched bases from sheared form to parallel form. Further analysis shows that the steric details of complex’s intercalation to base stack determine the results of recognition, which is induced by the steric collision among ancillary ligand phen, bases and DNA backbone, and by the steric crowding occurring in the process of structural expansion of bases and DNA backbone. Detailed analysis reveals that the conformational repair of mismatched bases relates not only to the steric interactions, but also the π-π stack among normal bases, mismatched bases and hpip ligand.     

原子类型电拓扑状态指数预测吲哚喹唑啉衍生物的抗癌性

采用原子类型电拓扑状态指数(ETSIAT)对17个吲哚喹唑啉衍生物的抗癌活性进行定量构效关系(QSAR)的研究. 经逐步回归变量筛选, 得到包含4个ETSIAT变量的最优偏最小二乘模型, 其复决定系数R2、留一法交互验证复决定系数Q2和均方根误差RMSEE分别为0.806、0.736 和0.248. 将样本随机分为训练集和预测集后, 采用相同变量组合对模型进行外部验证, 结果显示模型具有较高的外部预测能力. 模型分析结果显示, 与抗癌活性相关的4个ETSIAT描述子对应结构碎片分别为≥N=, —NH—, =O, >N—. 其中—NH—结构碎片与抗癌活性呈负相关关系, 而≥N=, >N—和=O则与抗癌活性呈正相关关系. 此外, 研究亦显示, 取代基R1上存在强的吸电子基团可显著提高化合物的抗癌活性, 且影响抗癌活性的因素可能还有R2基团的空间位阻效应. 据此设计出4个化合物的预测活性比最高活性样本分别提高7.7%、15.3%、23.1%和130%.     

Metal-intercalator-mediated self-association and one-dimensional aggregation in the structure of the excised major DNA adduct of a platinum-acridine agent

The crystal structure of the excised major DNA monoadduct, [Pt(en)(ACRAMTU-S)(dGuo-N7)]3+ ("dGuo*"; en = ethane-1,2-diamine; ACRAMTU = 1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea, acridinium cation; dGuo = 2'-deoxyguanosine), of a platinum-acridine cytotoxic agent is reported. The adduct dGuo*, previously identified in enzymatic digests of native DNA treated with this drug, is partially deprotonated and dimerizes through formation of a rare GG- mismatch base pair, which is sandwiched between the planar chromophores of the acridine nonleaving groups linked to platinum. NMR evidence exists that indicates that the dimeric form persists in neutral aqueous solution. The one-dimensional pi-stack produced by the dimers in the solid state is reminiscent of a coordinative-intercalative DNA binding mode.     

DNA cleavage activity of Fe(II)N4Py under photo irradiation in the presence of 1,8-naphthalimide and 9-aminoacridine: unexpected effects of reactive oxygen species scavengers

The DNA cleavage activity of the iron(II) complex of the ligand N,N-bis(2-pyridylmethyl)-N-bis(2-pyridyl)methylamine (N4Py) was investigated in the presence of the chromophores 1,8-naphthalimide (NI) and 9-aminoacridine (AA) under photo irradiation at 355 and 400.8 nm and compared to the activity of the complex without the chromophores. Whereas in most cases no synergistic effect of the added chromophores on DNA cleavage efficiency was observed, it was found that for Fe(II)N4Py, in combination with NI under irradiation at 355 nm, the DNA cleavage activity was increased. Surprisingly, it was found that the addition of reactive oxygen species (ROS) scavengers gave rise to significantly increased DNA cleavage efficiency, which is a highly counterintuitive observation since ROS are needed to achieve DNA cleavage. A hypothesis is put forward to explain, at least partly, these results. It is proposed that the addition of scavengers inhibits quenching of (3)NI*, thus making photo-induced electron transfer between (3)NI* and Fe(III)N4Py more efficient. This results in reduction of Fe(III)N4Py to Fe(II)N4Py, which can then react with ROS giving rise to DNA cleavage. Hence the role of the scavengers is to maintain a close to optimal concentration of ROS. The present study serves as an illustration of the care that needs to be exercised in interpreting the results of experiments using standard ROS scavengers, since especially in complex systems such as presented here they can give rise to unexpected phenomena. In the presence of 1,8-naphthalimide or 9-aminoacridine, ROS scavengers can increase the DNA cleavage efficiency of Fe(II)N4Py complex under photo irradiation.     

Palladium-catalyzed synthesis of nucleoside adducts from bay- and fjord-region diol epoxides

Palladium-catalyzed C-N bond formation has been utilized to synthesize covalent 2'-deoxyadenosine (dA) and 2'-deoxyguanosine (dG) adducts of benzo[a]pyrene (BaP) series 1 (syn) and benzo[c]phenanthrene (BcPh) series 2 (anti) diol epoxides. For this, (+/-)-10 alpha-amino-7 beta,8 alpha,9 beta-trisbenzoyloxy-7,8,9,10-tetrahydro BaP and (+/-)-1 beta-amino-2 alpha,3 alpha,4 beta-trisbenzoyloxy-1,2,3,4-tetrahydro BcPh were coupled with 6-halo-9-[3,5-bis-O-(tert-butyldimethylsilyl)-beta-D-erythro-pentofuranosyl]purine and O6-benzyl-3',5'-bis-O-(tert-butyldimethylsilyl)-2-bromo-2'-deoxyinosine, using a (+/-)-BINAP-Pd complex and Cs2CO3. For the synthesis of the dA adducts, both the 6-chloro- as well as the 6-bromopurine nucleoside derivatives were analyzed for the C-N coupling reaction with the hydrocarbon amino tribenzoates. With the BaP amino tribenzoate, the 6-chloronucleoside provided satisfactory results, whereas the 6-bromo analogue proved to be superior with the BcPh amino tribenzoate. Overall, lower yields of the dA adducts were obtained with the more hindered fjord-region BcPh amino tribenzoate as compared to the bay-region BaP amino tribenzoate. In contrast to reactions leading to the dA adducts, the C-N reactions of both BaP and BcPh amino tribenzoates with the 2-bromo-2'-deoxyinosine derivative proceeded in comparable yields. This seems to indicate that such Pd-catalyzed adduct forming reactions at the C-6 position may be influenced by steric constraints of the amine component, whereas those at the C-2 position are less sensitive. Diastereomeric adduct pairs were separated and characterized by spectral methods and by comparisons to adducts produced by direct displacement reactions as well as those formed from DNA alkylation by diol epoxides.     

Electronic spectral studies of molybdenyl complexes. 2. MCD spectroscopy of [MoOS4]- centers

Magnetic circular dichroism (MCD) and absorption spectroscopies have been used to probe the electronic structure of [PPh4][MoO(p-SC6H4X)4] (X = H, Cl, OMe) and [PPh4][MoO(edt)2] complexes (edt = ethane-1,2-dithiolate). The results of density functional calculations (DFT) on [MoO(SMe)4]- and [MoO(edt)2]- model complexes were used to provide a framework for the interpretation of the spectra. Our analysis shows that the lowest energy transitions in [MoVOS4] chromophores (S4 = sulfur donor ligand) result from S-->Mo charge transfer transitions from S valence orbitals that lie close to the ligand field manifold. The energies of these transitions are strongly dependent on the orientation of the S lone-pair orbitals with respect to the Mo atom that is determined by the geometry of the ligand backbone. Thus, the lowest energy transition in the MCD spectrum of [PPh4][MoO(p-SC6H4X)4] (X = H) occurs at 14,800 cm-1, while that in [PPh4][MoO(edt)2] occurs at 11,900 cm-1. The identification of three bands in the absorption spectrum of [PPh4][MoO(edt)2] arising from LMCT from S pseudo-sigma combinations to the singly occupied Mo 4d orbital in the xy plane suggests that there is considerable covalency in the ground-state electronic structures of [MoOS4] complexes. DFT calculations on [MoO(SMe)4]- reveal that the singly occupied HOMO is 53% Mo 4dxy and 35% S p for the equilibrium C4 geometry. For [MoO(edt)2]- the steric constraints imposed by the edt ligands result in the S pi orbitals being of similar energy to the Mo 4d manifold. Significant S pseudo-sigma and pi donation may also weaken the Mo identical to O bond in [MoOS4] centers, a requirement for facile active site regeneration in the catalytic cycle of the DMSO reductases. The strong dependence of the energies of the bands in the absorption and MCD spectra of [PPh4][MoO(p-SC6H4X)4] (X = H, Cl, OMe) and [PPh4][MoO(edt)2] on the ligand geometry suggests that the structural features of the active sites of the DMSO reductases may result in an electronic structure that is optimized for facile oxygen atom transfer.     

Helical self-assembled chromophore clusters based on DNA-like architecture

DNA duplexes were functionalized covalently by clusters of five adjacent chromophores consisting of 5-(pyren-1-yl)-2′-deoxyuridine (Py-U) and 5-(10-methyl-phenothiazin-3-yl)-2′-deoxyuridine (Pz-U). The chromophores form a regular helical π-array along the major groove of duplex DNA when the 5-fold chromophore-modified oligonucleotides are hybridized with an unmodified counter strand. As a result, these chromophores interact significantly and their fluorescence and absorption properties can be modulated by the sequence within the π-array. The 5-fold Py-U stack shows a strongly enhanced emission. The presence of intervening Pz-U groups quenches the fluorescence of the Py-U chromophores. Such modulation of the optical properties within a chromophore stack is potentially useful for optical nanodevices and as nucleic acid sensors for molecular diagnostics. The duplex architecture of DNA is suitable to provide the supramolecular structural scaffold for a directed arrangement of chromophores.     

Crystal Structures of trans-Tetrahydrotetrols of Benzo[a]pyrene and Chrysene: A Possible Structure-Activity Relationship in Quasi-Planar Bay-Region Polycyclic Aromatic Hydrocarbons

The molecular structures of two racemic trans-tetrahydrotetrols formed by hydrolysis of the (±)anti-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydro derivatives of the strong carcinogen benzo[a]pyrene and the weak carcinogen chrysene have been determined by X-ray crystallographic methods.³ Focusing on the (+)isomers, the stereochemical features of the two tetrols are discussed in detail to determine structural differences, which can be related to the different biological activity of their parent hydrocarbons, since they provide a model for the hydrocarbon moiety in the major PAH-DNA adduct. As a result of this study, a tentative correlation can be stated between biological activity of quasi-planar bay-region PAHs and the presence of structural features, which can decrease the steric hindrance of the aromatic skeleton and the other hydroxy groups on the pseudo-axial O4, which mimics the position of the covalent bond to DNA. The significant structural features seem to be an out-of-plane distortion with a negative torsion angle at the bay region and a half chair conformation of the saturated ring distorted toward the envelope with C8 at the tip as in BPT, in addition to the axial and pseudo-axial conformations of the hydroxy groups at C9 and C10 due to the near bay region. They may be considered generated by trans-opening of the oxirane ring in an anti-diol epoxide biologically active because it is highly strained. The strains, derived from the activation of bay-region PAHs with a negative torsion angle, seem greater in an anti-diol epoxide relative to the syn-isomer. Thus, when the strains are released, the derived trans-tetrol occurs with structural features, which seem to better fit the target. As a consequence, the presence of a methyl group at a bay region should increase the biological activity of a PAH, imposing greater strains to the structure of the anti-diol epoxide.     

Isodicyclopentadienes and related molecules : LVII. Solid state structural studies of the diastereomeric exo- and endo-(η -cyclopentadienyl)( η -( 1S,8R)-9,9-dimethyltricyclo[6.1.1.0]deca-2,5-dienyl) dichlorotitaniums and a stereopure exo-(η-pentamethyl-cyclopentadienyl) congener

The lithium salt of optically pure (1S,8R)-9,9-dimethyltricyclo[6.1.1.0^2,6]deca-2,5-diene (9) has been transformed in highly stereoselective fashion to the dichlorotitanium complexes 5–7. Temperature and reaction conditions can be suitably controlled to attain proper ρ-facial selectivity in those condensations involving CpTiCl₃. Direct condensation with CpTiCl₃, on the other hand, leads only to 7 in a more sluggish reaction. A stereochemical crossover to arrive at 8 was attempted by taking advantage of the inversion of configuration that operates during condensation of silane 10 with TiCl₄. Unfortunately, steric hindrance precluded the successful reaction of 11 with Cp^*M (M = Li, K, Tl, SiMe₃ SnMe₃) to provide 8. Crystal structure analyses of the three available complexes were completed and detailed comparison of their structural features are presented. The absolute configurational assignments rest securely on the synthetic pathway developed earlier for gaining access to 9.     

后叶催产素的定量构效关系研究

基于氨基酸物化性质的描述子矢量VHSE, 对21个后叶催产素类似物进行结构表征. 经逐步回归与偏最小二乘相结合的变量筛选技术, 根据模型的外部预测结果, 筛选得到一个最优的9变量组合. 应用该变量组合对21个后叶催产素类似物的促宫缩活性进行偏最小二乘建模, 模型复相关系数R2为92.6%, 留一法和留组法交互验证Q2分别为78.3%和79.4%. 结果表明, 后叶催产素的促宫缩活性主要与第3号氨基酸残基的疏水性、立体结构和电性性质以及第8号氨基酸残基的电性特征密切相关.     

The Bogorol family of antibiotics: template-based structure elucidation and a new approach to positioning enantiomeric pairs of amino acids

The sequence positions of d and l Leu and Lys residues in bogorol A (1) have been defined by a simple and novel approach that utilizes small amounts of sample and focuses on detecting the order in which amino acids are liberated from the parent peptide during acid-catalyzed hydrolysis. This technique builds on a previously established relationship between the steric and electronic features of amino acids and their predilection for acidic liberation from polypeptides via dipeptides. The results, which complete the structure of bogorol A, have been confirmed by traditional degradation experiments. Utilizing the knowledge of the structure of bogorol A (1) as a template, we rapidly elucidated the structures of bogorols B-E (2-5) via analysis of ESI-MS and ESI-MS/MS data and GC analysis of degradation products. The bogorol cationic peptide antibiotics contain a number of unusual structural features, which include the reduction of the C-terminal residue to valinol, an N-terminal residue of 2-hydroxy-3-methylpentanoic acid, the incorporation of four d amino acids, and the presence of a dehydroamino acid. Bogorols show selective and relatively potent activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus spp., as well as moderate activity against Escherichia coli.     

四甲基硅锗桥连双环戊二烯基及双(四甲基环戊二烯基)四羰 基二铁的合成、结 构及热重排反应

1,2-二氯四甲基硅锗烷分别与环戊二烯基锂及四甲基环戊二烯基锂反应得到两个新的双齿配体：C5H5Me2SiGeMe2C5H5(9)和C5HMe4Me2SiGeMe2C5HMe4(10).配体9和10分别与Fe(CO)5在二甲苯中加热生成四甲基硅锗桥连双环戊二烯基四羰基二铁(11)和四甲基硅锗桥连双(四甲基环戊二烯基)四羰基二铁(13).11和13均可发生热重排反应,生成[(η^5-C5R4)Fe(CO)2]2(μ-Me2Si)(μ-Me2Ge)(R=H,12;R=Me,14)。测定了化合物11,12,13及14的晶体结构,讨论了桥连四甲基环戊二烯基配体的位阻效应对其某些结构参数以及重排反应性的影响。     

Structure of the Complex of [Ru(tpm)(dppz)py]2+ with a B‐DNA Oligonucleotide—A Single‐Substituent Binding Switch for a Metallo‐Intercalator

We report the synthesis of three new complexes related to the achiral [Ru(tpm)(dppz)py]²⁺ cation (tpm=tripyridazole methane, dppz=dipyrido[3,2‐a:2′,3′‐c]phenazine, py=pyridine) that contain an additional single functional group on the monodentate ancillary pyridyl ligand. Computational calculations indicate that the coordinated pyridyl rings are in a fixed orientation parallel to the dppz axis, and that the electrostatic properties of the complexes are very similar. DNA binding studies on the new complexes reveal that the nature and positioning of the functional group has a profound effect on the binding mode and affinity of these complexes. To explore the molecular and structural basis of these effects, circular dichroism and NMR studies on [Ru(tpm)(dppz)py]Cl₂ with the octanucleotides d(AGAGCTCT)₂ and d(CGAGCTCG)₂, were carried out. These studies demonstrate that the dppz ligand intercalates into the G²–A³ step, with {Ru(tpm)py} in the minor groove. They also reveal that the complex intercalates into the binding site in two possible orientations with the pyridyl ligand of the major conformer making close contact with terminal base pairs. We conclude that substitution at the 2‐ or 3‐position of the pyridine ring has little effect on binding, but that substitution at the 4‐position drastically disrupts intercalative binding, particularly with a 4‐amino substituent, because of steric and electronic interactions with the DNA. These results indicate that complexes derived from these systems have the potential to function as sequence‐specific light‐switch systems.     

Systematic Studies on Homo- and Heteronuclear Doubly Bonded Compounds of Heavier Group 15 Elements

The first stable phosphabismuthene (R 1 --P=Bi--R 2 ) and stibabismuthene (R 1 --Sb=Bi--R 2 ) were successfully synthesized by taking advantage of efficient steric protection groups, 2,4,6-tris[bis(trimethylsilyl)methyl]phenyl (Tbt), 2,6-bis[bis(trimethylsilyl)-methyl]-4-[tris(trimethylsilyl)methyl]phenyl (Bbt), and 2,4,6-tri- t -butylphenyl (Mes*). Their spectroscopic properties and structural parameters were systematically compared with those of previously reported stable, homonuclear, doubly bonded systems, such as diphosphene, diarsene, distibene, and dibismuthene.     

Molecular modeling on recognition of sheared and normal DNA by novel metal complex Λ- and Δ-[Co(phen)2hpip]

Recognition of sheared and normal DNA by a novel metal complex [Co(phen)₂hpip]³⁺ (phen=1,10-phenanthroline, HPIP=2-(2-hydroxyphenyl)imidazole[4,5-f][1,10]phenanethroline) is studied by molecular modeling. Calculating results indicate that, this complex can specifically recognize DNA segment of sequence –MMNNMM– (M means mismatch base pairs and N means normal base pairs). Intercalating from minor groove between the middle normal duplex into the sheared DNA with the depth of 1.2 nm is of preference and enantioselectivity is observed. Comparison on the two DNA structures of optimal conformation and analysis on the interaction between DNA and the two tail ligands of the complex show that, the effect of the two neighboring mismatch duplexes on the structure of the middle normal base pairs and the steric interaction between the mismatch duplexes and the two tail ligands of the complex are the essential reason to the segment specificity. Investigation on the detailed energy terms indicate that, in effecting enantioselectivity, the electrostatic distribution of the complex is in the majority and steric interaction is at the next place. But, steric interaction is surely the only factor determining the intercalating from minor groove.