Observation of the reversibility of a covalent pyrrolobenzodiazepine (PBD) DNA adduct by HPLC/MS and CD spectroscopy

Pyrrolobenzodiazepines (PBDs) are sequence-selective DNA minor-groove binding agents that covalently bond to guanine with a reported preference for Pu-G-Pu sequences (Pu = Purine). Using HPLC/MS and Circular Dichroism (CD) methodologies, we have established for the first time that the aminal bond formed between PBD molecules and DNA is reversible. Furthermore, we have shown that while the rate of aminal bond cleavage does not depend on the sequence preference of a PBD molecule for a particular binding site, the rate of re-formation of the PBD-DNA adduct does. We have also shown that the PBD anthramycin (2) appears to be an exception to this rule in that, during cleavage from the DNA, its C-ring aromatizes and it cannot then re-attach due to a loss of electrophilicity at the C11-position. Although the C-ring aromatization of anthramycin has been previously reported to occur in the absence of DNA and after treatment with trifluoroacetic acid (TFA), in this case no pH lowering was required, with the DNA itself appearing to catalyse the process.     

Synthesis and characterization of soft–hard stereoblock polybutadiene with Fe(2‐EHA)3/Al(i‐Bu)3/DEP catalyst system

Stereoblock polybutadiene (PBD) composed of amorphous equibinary cis?1,4/1,2 PBD (e‐PBD, soft) and crystalline syndiotactic 1,2‐PBD (s‐1,2‐PBD, hard) segments is synthesized through one‐pot sequential polymerization with iron(III)2‐ethylhexanoate/triisobutylaluminum/diethyl phosphate [Fe(2‐EHA)₃/Al(i‐Bu)₃/DEP] catalyst system. The first‐stage polymerization of 1,3‐butadiene (BD) is carried out at a low [Al]/[Fe] ratio to give amorphous e‐PBD block, and sequentially, the in situ addition of excessive Al(i‐Bu)₃ and BD to the living polymerization system give rise to a second crystalline s‐1,2‐PBD block. The length of each block is controllable by adjusting cocatalyst and monomer feed ratio. The syndiotactic pentad content is in the range of 63.8–76.6% and increases with the length of s‐1,2‐PBD block. The copolymer exhibits glass transition temperature (T_g) around ?40 °C and melting point (T_m) around 168 °C originating from e‐PBD and s‐1,2‐PBD blocks, respectively. The incompatibility between s‐1,2‐PBD and e‐PBD blocks as well as the crystallization of s‐1,2‐PBD block induce the microphase separation in stereoblock PBD. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015 , 53, 1182–1188     

Tetrakis(diethyl‐phosphonat)‐, Tetrakis(ethyl‐phenylphosphinat)‐ und Tetrakis(diphenylphosphin‐oxid)‐substituierte Phthalocyanine

Tetrakis(diethyl phosphonate), Tetrakis(ethyl phenylphosphinate)‐, and Tetrakis(diphenylphosphine oxide)‐Substituted Phthalocyanines The title compounds 7, 9 , and 11 are obtained by tetramerization of diethyl (3,4‐dicyanophenyl)phosphonate ( 5 ), ethyl (3,4‐dicyanophenyl)phenylphosphinate ( 8 ), and 4‐(diphenylphosphinyl)benzene‐1,2‐dicarbonitrile ( 10 ). The ³¹P‐NMR spectra of the phthalocyanines 7, 9 , and 11 and of their metal complexes present five to eight signals confirming the formation of four constitutional isomers with the expected C_4h, D_2h, C_2v, and C_s symmetry. In the FAB‐MS of the Zn, Cu, and Ni complexes of 7 and 9 , the peaks of dimeric phthalocyanines are observed. By gel‐permeation chromatography, the monomeric complex [Ni( 7 )] and a dimer [Ni( 7 )]₂ can be separated. These dimers differ from the known phthalocyanine dimers, i.e., possibly the P(O)(OEt)₂ and P(O)(Ph)(OEt) substituents in 7 and 9 are involved in complexation. The free phosphonic acid complex [Zn( 12 )] and [Cu( 12 )] are H₂O‐soluble. In the FAB‐MS of [Zn( 12 )], only the peaks of the dimer are present; the ESI‐MS confirms the existence of the dimer and the metal‐free dimer. In the UV/VIS spectrum of [Zn( 12 )], the hypsochromic shift characteristic for the known type of dimers from 660–700 nm to 620–640 nm is observed. As in the FAB‐MS of [Zn( 12 )], the free phosphinic acid complex [Zn( 13 )] shows only the monomer, an ESI‐MS cannot be obtained for solubility problems. The UV/VIS spectrum of [Zn( 13 )] demonstrates the existence of the monomer as well as of the dimer.     

The Role of Organic Synthesis in the Emergence and Development of Antibody–Drug Conjugates as Targeted Cancer Therapies

With a number of antibody–drug conjugates (ADCs) approved for clinical use as targeted cancer therapies and numerous candidates in clinical trials, the field of ADCs is emerging as one of the frontiers in biomedical research, particularly in the area of cancer treatment. Chemists, biologists and clinicians, among other scientists, are partnering their expertise to improve their design, synthesis, efficacy and precision as they strive to advance this paradigm of personalized and targeted medicine to treat cancer patients more effectively and to expand its scope to other indications. Just as Alexander Fleming's penicillin, and the myriad other bioactive natural products that followed its discovery and success in the clinic, ignited a revolution in medicine after the Second World War, so did calicheamicin γ₁^I, and other highly potent naturally occurring antitumor agents, play a pivotal role in enabling the advent of this new paradigm of “biological‐small molecule hybrid” medical intervention. Today there are four clinically approved drugs from the ADC paradigm, Mylotarg, Adcetris, Kadcyla and Besponsa, in order of approval, the first and the last of which carry the same calicheamicin γ₁^I‐derived payload. Covering oncological applications, and after a brief history of the emergence of the field of antibody–drug conjugates triggered more than a century ago by Paul Ehrlich's “magic bullet” concept, this Review is primarily focusing on the chemical synthesis aspects of the ADCs multidisciplinary research enterprise.     

Electroluminescent Properties of an Electrochemically Cross‐Linkable Carbazole Peripheral Poly(Benzyl Ether) Dendrimer

The electroluminescent (EL) properties of a cross‐linkable carbazole‐terminated poly(benzyl ether) dendrimer, G₃‐cbz DN, doped into a PVK:PBD host matrix with a double‐layer device configuration are investigated. Different concentrations of the guest material can control device efficiency, related to chromaticity of white emission and the origin of excited‐state complexes occurring between hole‐transporting carbazole units (PVK or G₃‐cbz DN) and electron‐transporting oxadiazole (PBD). Two excited states (exciplex and electroplex) generated at the interfaces of PVK/G₃‐cbz DN and PBD result in competitive emission, exhibiting a broad band in the EL spectra.     

齐聚噻吩衍生物电致变色性质

合成了四种齐聚噻吩衍生物：5,5"-二氰基-2,2’:5’,2"-三噻吩 (DCN3T), 5,5"’-二氰基-2,2’:5’,2":5",2"’-四噻吩 (DCN4T), 5,5"’-甲氧基-2,2’:5’,2":5",2"’-四噻吩(DMO4T) 和 4,4"-二羧基-5,5"-二丙基-2,2’:5’,2"-三噻吩 (BP3T-DCOOH),研究了它们的电致变色性质,研究结果发现,这四种齐聚噻吩衍生物膜在电场作用下,可以发生可逆的颜色变化。     

Bis‐copper(II) Complex of Triply‐linked Corrole Dimer and Its Dication

Copper complexes of corroles have recently been a subject of keen interest due to their ligand non‐innocent character and unique redox properties. Here we investigated bis‐copper complex of a triply‐linked corrole dimer that serves as a pair of divalent metal ligands but can be reduced to a pair of trivalent metal ligands. Reaction of triply‐linked corrole dimer 2 with Cu(acac)₂ (acac=acetylacetonate) gave bis‐copper(II) complex 2Cu as a highly planar molecule with a mean‐plane deviation value of 0.020 Å, where the two copper ions were revealed to be divalent by ESR, SQUID, and XPS methods. Oxidation of 2Cu with two equivalents of AgBF₄ gave complex 3Cu , which was characterized as a bis‐copper(II) complex of a dicationic triply‐linked corrole dimer not as the corresponding bis‐copper(III) complex. In accord with this assignment, the structural parameters around the copper ions were revealed to be quite similar for 2Cu and 3Cu . Importantly, the magnetic spin–spin interaction differs depending on the redox‐state of the ligand, being weak ferromagnetic in 2Cu and antiferromagnetic in 3Cu .     

Double Pancake Versus Long Chalcogen–Chalcogen Bonds in Six‐Membered C,N,S‐Heterocycles

The double “pancake” bonding in the dimers of the six‐membered heterocycles 1,3‐dithia‐2,4,6‐triazine ( 4 ) and 1,3‐dithia‐2,4‐diazine ( 16 ) were investigated by means of high‐level quantum chemical calculations (B3LYP and CCSD(T)). It was found that the S–S dimers, 20 a and 27 , are not the most stable isomers, but the dimers showing short S?N ( 21 a ) and S?C ( 25 , 28 ) bonds. An investigation of the 5‐phenyl‐1,3‐dithia‐2,4,6‐triazine ( 4 b ) yields that the syn dimer with two S?S bonds (2.57 Å) is the most stable one. In this dimer, the phenyl groups are placed on top of each other. The additional dispersion energy of the phenyl rings causes a stabilization of the syn‐S–S (C_2v‐like) isomer. As a result, two weak albeit relevant single S?S bonds (2.57 Å) are predicted. These findings contradict the recently published concept of double “pancake” bonding in the dimer 4 b ₂.     

Solid‐State Structure of a Li/F Carbenoid: Pentafluoroethyllithium

Lithium carbenoids are versatile compounds for synthesis owing to their intriguing ambiphilic behavior. Although this class of compounds has been known for several years, few solid‐state structures exist because of their high reactivity and often low thermal stability. Using cryo X‐ray techniques, we were now able to elucidate the first solid‐state structure of a Li/F alkyl carbenoid, pentafluoroethyllithium (LiC₂F₅), finally yielding a prototype for investigating structure—reactivity relationships for this class of molecules. The compound forms a diethyl ether‐solvated dimer bridged by a rare C–F–Li link. Complementary NMR spectroscopy studies in solution show dynamic processes and indicate rapid exchange of starting material and product. Theoretical investigations help to understand the formation of the observed unusual structural motif.     

Antibody–Drug Conjugates: An Emerging Concept in Cancer Therapy

Traditional cancer chemotherapy is often accompanied by systemic toxicity to the patient. Monoclonal antibodies against antigens on cancer cells offer an alternative tumor‐selective treatment approach. However, most monoclonal antibodies are not sufficiently potent to be therapeutically active on their own. Antibody–drug conjugates (ADCs) use antibodies to deliver a potent cytotoxic compound selectively to tumor cells, thus improving the therapeutic index of chemotherapeutic agents. The recent approval of two ADCs, brentuximab vedotin and ado‐trastuzumab emtansine, for cancer treatment has spurred tremendous research interest in this field. This Review touches upon the early efforts in the field, and describes how the lessons learned from the first‐generation ADCs have led to improvements in every aspect of this technology, i.e., the antibody, the cytotoxic compound, and the linker connecting them, leading to the current successes. The design of ADCs currently in clinical development, and results from mechanistic studies and preclinical and clinical evaluation are discussed. Emerging technologies that seek to further advance this exciting area of research are also discussed.     

Bis(dimethyl sulfoxide‐S)tetrakis(μ‐p‐hydroxybenzoato‐O:O′)dirhodium(II)–tetrakis(μ‐butyrato‐O:O′)bis(dimethyl sulfoxide‐S)dirhodium(II) cocrystal ethanol disolvate

The title structure, [Rh₂(C₇H₅O₃)₄(C₂H₆OS)₂]·[Rh₂(C₄H₇­O₂)₄(C₂H₆OS)₂]·2C₂H₆O, contains two discrete neutral Rh–Rh dimers cocrystallized as the ethanol disolvate. Each dimer is situated on an inversion center. The butyrate chain displays disorder in one C‐atom position. In each dimer, the di­methyl sulfoxide ligand (dmso) is bound via S, as expected. The ethanol is a hydrogen‐bond acceptor for one p‐hydroxy­benzoate hydroxyl group and acts as a hydrogen‐bond donor to the dmso O atom of a neighboring p‐hydroxy­benzoate dirhodium complex. A third hydrogen bond is formed from the other p‐hydroxy­benzoate hydroxyl group to the dmso O atom of a butyrate–dirhodium complex.     

1,4‐Dilithio‐1,1,4,4‐tetraphenylbutane in diethyl ether: An effective initiator for the living anionic polymerization of dienes

The anionic polymerization of butadiene initiated with 1,4‐dilithio‐1,1,4,4‐tetraphenylbutane (LiTPB) in diethyl ether (DEE) gives polybutadiene (PBD) with high 1,2 content (>70%), narrow polydispersities (1.04 < M_w/M_n < 1.20), and predicted molecular weights. In THF, this polymerization does not work very well. After removal of DEE and addition of THF, the PBD dianion is end capped quantitatively by addition of 1,1‐diphenylethylene (DPE) to give the diphenylalkyl end capped PBD dianion. Subsequent addition of methyl methacrylate at low temperatures results in the formation of well‐defined PMMA‐b‐PBD‐b‐PMMA triblock copolymers. The results are accounted for by taking into account the effects of Li ion solvation on the BD initiation and end capping of the PBD anion by DPE. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 2198–2206, 2009     

meso–meso‐Linked Diarylamine‐Fused Porphyrin Dimers

A meso–meso‐linked diphenylamine‐fused porphyrin dimer and its methoxy‐substituted analogue were synthesized from a meso–meso‐linked porphyrin dimer by a reaction sequence involving Ir‐catalyzed β‐selective borylation, iodination, meso‐chlorination, and S_NAr reactions with diarylamines followed by electron‐transfer‐mediated intramolecular double C?H/C?I coupling. While these dimers commonly display characteristic split Soret bands and small oxidation potentials, they produced different products upon oxidation with tris(4‐bromophenyl)aminium hexachloroantimonate. Namely, the diphenylamine‐fused porphyrin dimer was converted into a dicationic closed‐shell quinonoidal dimer, while the methoxy‐substituted dimer gave a meso–meso, β‐β doubly linked porphyrin dimer.     

A quadrupole–quadrupole stacking synthon in (2,3,5,6‐tetra­fluorobenzene­thiol­ato‐κS)(tri­phenylphosphine‐κP)­gold(I)

The title compound, [Au(C₆HF₄S)(C₁₈H₁₅P)], with both aromatic and fluorinated aromatic rings in its molecular system, shows dimerization through a quadrupole–quadrupole stacking synthon. The dimer further aggregates through intermolecular π–π stacking and C—H⋯π interactions, giving a supramolecular three‐dimensional network.     

Investigation of the Benzene–Naphthalene and Naphthalene–Naphthalene Potential Energy Surfaces: DFT/CCSD(T) Correction Scheme

The potential energy surfaces of the naphthalene dimer and benzene–naphthalene complexes are investigated using the recently developed DFT/CCSD(T) correction scheme [J. Chem. Phys. 2008 , 128, 114 102]. One and three minima are located on the PES of the benzene–naphthalene and the naphthalene dimer complexes, respectively, all of which are of the parallel‐displaced type. The stabilities of benzene–naphthalene and the naphthalene dimer are ?4.2 and ?6.2 kcal mol^?1, respectively. Unlike the benzene dimer, where the T‐shaped complex is the global minimum, the lowest‐energy T‐shaped structure is about 0.2 and 1.6 kcal mol^?1 above the global minimum on the benzene–naphthalene and the naphthalene dimer potential energy surfaces, respectively.     

Synthesis of poly(3‐hexylthiophene)‐block‐poly(ethylene)‐block‐poly(3‐hexylthiophene) via a combination of ring‐opening olefin metathesis polymerization and grignard metathesis polymerization

Novel rod–coil–rod ABA triblock copolymers, poly(3‐hexylthiophene)‐block‐poly(ethylene)‐block‐poly(3‐hexylthiophene) (P3HT‐b‐PE‐b‐P3HT) were synthesized by using a combination of a Ru‐catalyzed ring‐opening metathesis polymerization of 1,4‐cyclooctadiene in the presence of a suitable chain transfer agent (CTA) and a Ni‐catalyzed Grignard metathesis polymerization of 5‐chloromagnesio‐2‐bromo‐3‐hexylthiophene followed by hydrogenation. Using this methodology, the molecular weights of the poly(butadiene) (PBD) or the P3HT blocks were controlled by adjusting the initial monomer/CTA or the initial monomer/macroinitiator ratio, respectively. In addition, the triblock structure was confirmed by selective oxidative degradation of the PBD block found in the intermediate P3HT‐b‐PBD‐b‐P3HT copolymer produced in the aforementioned method, followed by analysis of the degradation products. Thermal analysis and atomic force microscopy of P3HT‐b‐PE‐b‐P3HT revealed that the material underwent phase separation in the solid state, a feature which may prove useful for improving charge mobilities within electronic devices. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013 , 51, 3810–3817     

Boosting Low‐Valent Aluminum(I) Reactivity with a Potassium Reagent

The reagent RK [R=CH(SiMe₃)₂ or N(SiMe₃)₂] was expected to react with the low‐valent (^DIPPBDI)Al (^DIPPBDI=HC[C(Me)N(DIPP)]₂, DIPP=2,6‐iPr‐phenyl) to give [(^DIPPBDI)AlR]^?K⁺. However, deprotonation of the Me group in the ligand backbone was observed and [H₂C=C(N‐DIPP)?C(H)=C(Me)?N?DIPP]Al^?K⁺ ( 1 ) crystallized as a bright‐yellow product (73 %). Like most anionic Al^I complexes, 1 forms a dimer in which formally negatively charged Al centers are bridged by K⁺ ions, showing strong K⁺???DIPP interactions. The rather short Al–K bonds [3.499(1)–3.588(1) Å] indicate tight bonding of the dimer. According to DOSY NMR analysis, 1 is dimeric in C₆H₆ and monomeric in THF, but slowly reacts with both solvents. In reaction with C₆H₆, two C?H bond activations are observed and a product with a para‐phenylene moiety was exclusively isolated. DFT calculations confirm that the Al center in 1 is more reactive than that in (^DIPPBDI)Al. Calculations show that both Al^I and K⁺ work in concert and determines the reactivity of 1 .     

A hydrogen‐bonded dimer of 13‐hydroxy‐13‐[(triisopropyl­silyl)­ethynyl]penta­cen‐6(13H)‐one

The title compound, C₃₃H₃₄O₂Si, has been obtained as a product in the synthesis of 6,13‐bis­[(triisopropyl­silyl)ethynyl]‐6,13‐dihydro­penta­cene‐6,13‐diol. The solid‐state structure reveals a dimer, with strong hydrogen bonds holding the two mol­ecules in a face‐to‐face arrangement [O⋯O = 2.746 (2) Å and O—H⋯O = 173 (2)°]. Within each dimer, the penta­cene units are π‐stacked (the distance between the mean least‐squares planes of 22 C atoms is 3.60 Å).     

Tri­phenyl(3,4,5‐tri­iodo­phenyl)­methane

The crystal structure of the title compound, alternatively called 1,2,3‐triiodo‐5‐(triphenylmethyl)benzene, C₂₅H₁₇I₃, is analysed in terms of I⋯I and I⋯π interactions and the herring‐bone T motif between phenyl groups. There are two mol­ecules in the asymmetric unit, denoted A and B. Inversion‐related A mol­ecules are connected via an I⋯π interaction (3.641 Å, to a C—C bond mid‐point) to form an I⋯π dimer, and these dimers are connected through symmetry‐independent B mol­ecules via I⋯I [3.5571 (15) Å] and I⋯π (3.561 Å, to a C—C bond mid‐point) interactions.     

Well‐Defined Four‐Coordinate Iron(II) Complexes For Intramolecular Hydroamination of Primary Aliphatic Alkenylamines

Despite the growing interest in iron catalysis and hydroamination reactions, iron‐catalyzed hydroamination of unprotected primary aliphatic amines and unactivated alkenes has not been reported to date. Herein, a novel well‐defined four‐coordinate β‐diketiminatoiron(II) alkyl complex is shown to be an excellent precatalyst for the highly selective cyclohydroamination of primary aliphatic alkenylamines at mild temperatures (70–90 °C). Both empirical kinetic analyses and the reactivity of an isolated iron(II) amidoalkene dimer, [LFe(NHCH₂CPh₂CH₂CH?CH₂)]₂ favor a stepwise σ‐insertive mechanism that entails migratory insertion of the pendant alkene into an iron–amido bond associated with a rate‐determining aminolysis step.