Solubilizing Moiety Research Articles

An efficient solution-processable hybridized local and charge-transfer (HLCT)-based deep-red fluorescent emitter for simple structured non-doped OLED

The development of highly efficient deep-red fluorescent emitters is still a challenging task due to their intrinsic low bandgap characteristics resulting in low fluorescence emission in solid-state. Moreover, most of efficient deep-red organic light-emitting diodes (OLEDs) have complex device structures and are fabricated by high-cost vacuum deposition techniques. Herein, a novel solution-processable hybridized local and charge-transfer (HLCT) deep-red fluorescent molecule, TPA-NZF, is designed and synthesized as an emitter for low-cost and simple-structured OLEDs. TPA-NZF comprises a strong electron-deficient naphthothiadiazole (NZ) functionalized with triphenylamine (TPA) as a donor and dioctylfluorene as a solubilizing moiety. The photophysical results and theoretical calculations reveal a strong donor-acceptor feature and deep-red fluorescent emission with a solid-state photoluminescence quantum yield as high as 44%, decent hole-transporting mobility, good film morphology, and thermal and electrochemical stabilities. TPA-NZF is successfully fabricated as a solution-processed non-doped emitter in simple structured OLEDs. The device shows excellent electroluminescence (EL) performance (maximum external quantum efficiency (EQEmax) of 3.59%) and a deep-red emission with CIE coordinates of (0.66, 0.33).

Abstract 734: Thienoindoles: New highly promising agents for antibody-drug conjugates generation

Abstract Thienoindoles are a new proprietary class of highly potent DNA minor groove alkylating agents. This class is characterized by a fused thiophene ring whose intrinsic electron-withdrawing character provides a nearly optimal increase in stability and potency of alkylating subunits. Furthermore, the presence of a solubilizing moiety on the minor groove portion provides compounds with physicochemical properties highly compatible with deployment as antibody payloads. Extensive optimization of this class has led to the identification of the highly potent toxin NMS-P528 with sub-nanomolar IC50 in proliferation assay across a large panel of tumor cell lines. NMS-P945, a drug-linker generated from NMS-P528, is highly suited for conjugation with targeted antibodies, consistently yielding ADCs with favorable drug-antibody ratios in the absence of significant antibody aggregation and with full maintenance of antigen binding capability. Proof of concept efficacy and mechanism of action studies were performed using NMS-P945 conjugated with trastuzumab, observing for the resulting conjugate excellent in vitro target-directed cytotoxicity in HER2-positive vs. negative cancer cell lines. In animal efficacy studies against HER2-positive human breast cancer tumors, trastuzumab-NMS-P945 ADC administration yielded complete tumor regression with no effects on body weight gain, while unarmed trastuzumab and armed control antibody showed little and no effect, respectively. PK data indicated long plasma half-life of our novel ADCs in the monkey. Promising results were also obtained with a range of different antibody/antigen systems, e.g. with an antibody directed to the ALK receptor tyrosine kinase. Extensive process research has been completed for the production of NMS-P528 and NMS-P945, resulting in an efficient stereoselective method for the preparation of GMP materials on the 100g scale and both products are proposed as a licensing opportunity for conjugation with tumor-targeting antibodies. Citation Format: Michele Caruso, Fabio Gasparri, Barbara Valsasina, Clara Albanese, Italo Beria, Ilaria Candiani, Marina Ciomei, Nicoletta Colombo, Sabrina Cribioli, Ulisse Cucchi, Eduard Felder, Ivan Fraietta, Arturo Galvani, Antonella Isacchi, Aurelio Marsiglio, Paolo Orsini, Rita Perego, Simona Rizzi, Attilio Tomasi, Sonia Troiani, Carlo Visco, Daniele Donati. Thienoindoles: New highly promising agents for antibody-drug conjugates generation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 734.

Semi-crystalline A1–D–A2-type copolymers for efficient polymer solar cells

A series of acceptor1–donor–acceptor2 (A1–D–A2)-type copolymers was designed and synthesized using thiophene as an electron-rich unit and benzothiadiazole (BT) and benzotriazole (BTz) as electron-deficient moieties. A weaker acceptor, BTz, was incorporated as a solubilizing moiety with three tetradecyl (or tetradecyloxy) side chains, and a stronger acceptor, BT, was substituted with different numbers of fluorines to modulate the intramolecular charge transfer interaction and the resulting electronic structures. The similar molecular structures of BT and BTz did not disrupt the interchain organization significantly, and the absence of solubilizing alkyl substituents on the electron-rich thiophene did not increase the highest occupied molecular orbital of the resulting polymers. The polymers showed broad absorption in the range of 350–750 nm. Intra- and/or interchain non-covalent coulombic interactions (for example, dipole–dipole interactions via S···O, S···F) ensured a planar backbone and a semi-crystalline morphology in the film. Bulk heterojunction polymer solar cells were fabricated using blends of the polymers and phenyl-C71-butyric acid methyl ester (PC71BM). For a difluoro-BT containing polymer (BTzDT2FBT), a power conversion efficiency up to 7% was achieved with a short circuit current density of 14.64 mA cm−2, open circuit voltage of 0.75 V and fill factor of 0.64. Three types of A1–D–A2 conjugated polymers were synthesized based on thiophene as an electron-rich unit and two similarly structured electron-deficient moieties of benzothiadiazole (BT) and benzotriazole (BTz). The weaker acceptor, BTz, with three alkyl (or alkyloxy) substituents took on a solubilizing role without deteriorating the chain planarity. The absence of alkyl substituents on thiophene induced a deep valence band. Increasing the number of fluorine substituents on BT decreased the frontier orbitals and enhanced the interchain packing. The chain planarity and crystalline interchain organization were facilitated via intra- and/or interchain non-covalent S···O and S···F coulombic interactions. The best power conversion efficiency of 7% was measured for BTzDT2FBT:PC71BM.

Water‐Soluble Nitric‐Oxide‐Releasing Acetylsalicylic Acid (ASA) Prodrugs

A series of water-soluble (benzoyloxy)methyl esters of acetylsalicylic acid (ASA), commonly known as aspirin, are described. The new derivatives each have alkyl chains containing a nitric oxide (NO)-releasing nitrooxy group and a solubilizing moiety bonded to the benzoyl ring. The compounds were synthesized and evaluated as ASA prodrugs. After conversion to the appropriate salt, most of the derivatives are solid at room temperature and all possess good water solubility. They are quite stable in acid solution (pH 1) and less stable at physiological pH. In human serum, these compounds are immediately metabolized by esterases, producing a mixture of ASA, salicylic acid (SA), and of the related NO-donor benzoic acids, along with other minor products. Due to ASA release, the prodrugs are capable of inhibiting collagen-induced platelet aggregation of human platelet-rich plasma. Simple NO-donor benzoic acids 3-hydroxy-4-(3-nitrooxypropoxy)benzoic acid (28) and 3-(morpholin-4-ylmethyl)-4-[3-(nitrooxy)propoxy]benzoic acid (48) were also studied as representative models of the whole class of benzoic acids formed following metabolism of the prodrugs in serum. These simplified derivatives did not trigger antiaggregatory activity when tested at 300 μM. Only 28 displays quite potent NO-dependent vasodilatatory action. Further in vivo evaluation of two selected prodrugs, {[2-(acetyloxy)benzoyl]oxy}methyl-3-[(3-[aminopropanoyl)oxy]-4-[3-(nitrooxy)propoxy]benzoate⋅HCl (38) and {[2-(acetyloxy)benzoyl]oxy}methyl 3-(morpholin-4-ylmethyl)-4-[3-(nitrooxy)propoxy]benzoate oxalate (49), revealed that their anti-inflammatory activities are similar to that of ASA when tested in the carrageenan-induced paw edema assay in rats. The gastrotoxicity of the two prodrugs was also determined to be lower than that of ASA in a lesion model in rats. Taken together, these results indicated that these NO-donor ASA prodrugs warrant further investigation for clinical application.

Pyrazolo[3,4-d]pyrimidine Prodrugs: Strategic Optimization of the Aqueous Solubility of Dual Src/Abl Inhibitors

Design and synthesis of prodrugs of promising drug candidates represents a valid strategy to overcome the lack of favorable ADME properties, in particular aqueous solubility and bioavailability. We report herein the successful application of this strategy with two representative pyrazolo[3,4-d]pyrimidine derivatives (1 and 2), which led to the development of the corresponding and highly water-soluble antitumor prodrugs (7 and 8). In vitro studies confirmed a significant improvement of aqueous solubility and, for compound 8, good plasma stability, suggesting superior in vivo bioavailability. As expected, the uncleaved water-soluble prodrugs 7 and 8 showed no activity toward the enzymatic targets (c-Src and c-Abl) but revealed promising antiproliferative activity in myeloid cell lines, as a consequence of the in vitro hydrolysis of the selected solubilizing moiety, followed by the release of the active compounds (1 and 2).

Boron Subphthalocyanine Dyes: 3-Pentadecylphenol as a Solubilizing Molecular Fragment

We report the synthesis and characterization of a series of boronsubphthalocyanine (BsubPc) dyes which have organic solubility >10–2 M while being amenable to doping into polymeric films. To achieve high solubility we have placed the 3-pentadecylphenoxy molecular fragment in a variety of positions within the BsubPc chemical structure including around the periphery of the BsubPc ligand and in the axial position to the boron atom. We have found that placement of the 3-pentadecylphenoxy molecular fragment around the periphery adversely affects the photostability of the resulting BsubPc whereas placement in the axial position has little effect. We also confirm that the presence of fluorine atoms around the periphery improves the photostability. Overall we present a systematic study of the 3-pentadecylphenoxy fragment as a solubilizing moiety for BsubPc. The nature of the substituents and their position does not affect the nearly pure magenta color characteristic of BsubPc derivatives.

Effects of Fatty Acid Bile Acid Conjugates (FABACs) on Biliary Lithogenesis: Potential Consequences for Non-Surgical Treatment of Gallstones

Fatty acid bile acid conjugates (FABACs) are novel synthetic lipid molecules, which were designed for the treatment of cholesterol gallstones. The rationale was to combine a cholesterol solubilizing moiety (a saturated fatty acid) with a bile acid (cholic acid) as a vehicle to enable secretion into bile and entry into the enterohepatic circulation. An amide bond was used to provide stability against intestinal degradation. Initial in vitro studies showed that FABACs are indeed cholesterol solubilizers, able to prevent biliary cholesterol crystallization. Arachidyl-amido-cholanoic acid (Aramchol) was found to be the most potent FABAC in these studies. Animal studies revealed that Aramchol was absorbed after oral administration and could prevent cholesterol crystallization as well as dissolve preformed crystals in rodents fed a lithogenic diet. In gallstone susceptible mice, Aramchol prevented gallstone formation and dissolved gallstones. FABACs were found to be metabolically active substances, also able to decrease blood cholesterol, atherosclerotic plaques and fat accumulation in the liver in several animal species. The underlying mechanisms of action are under active investigation, and several effects, e.g. on cholesterol and bile salt metabolizing enzymes as well as cholesterol efflux from cells have been discovered. These findings are, however, only the beginning of our understanding of the metabolic actions as well as the potential of use of FABACs as therapeutic agents.

Water‐soluble prodrugs of cyclosporine A with tailored conversion rates

A novel type of water-soluble prodrugs of cyclosporine A (CsA) is described, featuring a modular system of an enzyme-cleavable group, a solubilizing moiety and a chemodegradable spacer attached to the hydroxyl function of (4R)-4-[(E)-2-butenyl]-4-,N-dimethyl-l-threonine (MeBmt)-1 of CsA. The chemical synthesis of these double prodrugs proceeds in high yield and purity and allows for a systematic study of the influence of the structural parameters upon physicochemical and pharmacological properties. The evaluation of the chemical and enzymatic stability results in differential values of the conversion rates (minutes to several hours) in support of an enzyme-triggered release of the parent drug as the rate-limiting step. In vitro studies show that the designed prodrug systems can be regarded as soft prodrugs in being devoid of cyclophiline A (CypA) binding and that complete conversion to the parent drug occurs in whole rat blood, setting the stage for therapeutic use.

Polysiloxane‐Bound Ligand Accelerated Catalysis: A Modular Approach to Heterogeneous and Homogeneous Macromolecular Asymmetric Dihydroxylation Ligands.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Conversion of cyclosporine A prodrugs in human tears vs rabbits tears

The aim of this study was to evaluate the rate and mechanism of conversion of two water-soluble prodrugs of cyclosporine A (CsA) intended for topical delivery to the eye. The new molecules were designed according to the double prodrug concept: a solubilizing moiety was grafted onto CsA via an ester function, which could be hydrolysed via a two-step process (enzymatic and chemical). Prodrug solutions were prepared extemporaneously in an isotonic and neutral aqueous medium compatible with ophthalmic use. The rates of conversion into the parent molecule were determined by incubating the prodrugs in fresh rabbit or human tears or in a phosphate buffer solution (PBS) at pH 7.4. Both prodrugs were converted into CsA within the first minute in the presence of rabbit tears with rate constants of k=5.9×10 −3 min −1 and k=3.8×10 −3 min −1, respectively, for UNIL088 and UNIL089, whereas chemical conversion in PBS was negligible ( k=0.5×10 −3 min −1 for both molecules). Incubation of UNIL088 in human tears showed a significantly high conversion rate. It is concluded that the developed double prodrugs underwent a bioconversion in physiological media and thus represent promising candidates for topical delivery of CsA to the eye.

Polysiloxane-bound ligand accelerated catalysis: a modular approach to heterogeneous and homogeneous macromolecular asymmetric dihydroxylation ligands.

Polysiloxane acts as a modular scaffold for macromolecular reagent development. Two separate components were covalently integrated into one material, one constituent provided reagent functionality, the other modulated solubility. In particular cinchona alkaloid based ligands used in the osmium tetroxide catalyzed asymmetric dihydroxylation (AD) reaction were covalently attached to commercially available polysiloxane. To enhance the reactivity of these polymeric ligands, multifunctional reagents were designed to include both the cinchona alkaloid and an alkoxyethylester solubilizing moiety providing random co-polymers. While the mono-functional materials led to heterogeneous conditions, the bi-functional polymers resulted in homogeneous reaction mixtures. Although both reagent types provided diol products with excellent yield and selectivity (>99% ee in nearly quantitative yield) the homogeneous analog has nearly twice the reactivity. Every repeat unit in the heterogeneous material was functionalized along the polysiloxane backbone while approximately half of these sites contained ligand in the homogeneous version. This approach led to macromolecular catalysts with high loadings of ligand and therefore materials with very low equivalent weights. Although these polymers are highly loaded they do maintain reactivity on a par with their free ligand counterpart. Using straightforward purification techniques (i.e. precipitation, simple filtration, or ultrafiltration) these polymeric ligands were easily separated from diol product and reused multiple times. Polysiloxane is a viable support for the catalysis of AD reactions and may provide a generally useful backbone for other catalytic systems.

ChemInform Abstract: Controlled Drug Release: New Water‐Soluble Prodrugs of an HIV Protease Inhibitor.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Controlled drug release: new water-soluble prodrugs of an HIV protease inhibitor

We designed and synthesized a series of highly water-soluble prodrugs of an HIV protease inhibitor, KNI-727 ( 1), containing tandem-linked two auxiliary units, a solubilizing moiety and a self-cleavable spacer. Prodrugs with an ionized amino group at the solubilizing moiety exhibited a remarkable increase of water-solubility (>10 4 fold) compared to the parent drug 1. These prodrugs released 1 not enzymatically, but chemically via an intramolecular cyclization-elimination reaction through an imide formation in physiological conditions. Diversified rates of parent drug release were observed when the chemical structure of both the solubilizing and the spacer moieties were modified. This new approach for water-soluble prodrugs will enable to control chemically the release of parent drug as well as to maintain high water-solubility.

Antimalarial activity of new water-soluble dihydroartemisinin derivatives.

The usefulness of sodium artesunate (3), a water-soluble derivative of artemisinin (1), is impaired by its poor stability in aqueous solution. To overcome the ease of hydrolysis of the ester group in 3, a new series of derivatives of dihydroartemisinin (2) was prepared in which the solubilizing moiety, which contains a carboxylate group, is joined to dihydroartemisinin by an ether rather than an ester linkage. The new derivatives were prepared in good yield by treatment of dihydroartemisinin with an appropriate alcohol under boron trifluoride etherate catalysis at room temperature. All major condensation products are the beta isomer. Hydrolysis of the esters with 2.5% KOH/MeOH gave the corresponding potassium salts, which were converted to free acids (8b-d) by acidification. The derivatives were tested in vitro against two clones of human malaria, Plasmodium falciparum D-6 (Sierra Leone clone) and W-2 (Indochina clone). No cross-resistance to the antimalarial agents mefloquine, chloroquine, pyrimethamine, sulfadoxine, and quinine was observed. In general, the new compounds are more effective against the W-2 than the D-6 strain. Esters (5a-d) possess activity comparable to that of the parent compounds 1 and 2; however, conversion of the esters to their corresponding carboxylates (7a-d) or acids (8b-d), with the exception of artelinic acid (8d), drastically decreases the antimalarial activities in both cell lines. Artelinic acid, which is both soluble and stable in 2.5% K2CO3 solution, possesses superior in vivo activity against Plasmodium berghei than artemisinin or artesunic acid.

Strategies in the Design of Solution-Stable, Water-Soluble Prodrugs Ill: Influence of the Pro-Moiety on the Bioconversion of 21-Esters of Corticosteroids

Succinate esters and many other carboxylic acid esters utilized as water-soluble prodrugs have limited utility due to their aqueous solution instability. In an earlier study, a strategy for the design of solution-stable 21-carboxylic acid esters of corticosteroids was developed from a consideration of various physical organic factors which influence ester hydrolysis. Several 21-esters of methylprednisolone were synthesized, and their stability in aqueous solution was monitored to demonstrate the feasibility of the approach. In this study, the bioconversion of representative examples of 21-esters of methylprednisolone exhibiting shelf lives of >2 years at 25°C was monitored to evaluate their utility as prodrugs in comparison to a commercially marketed sodium succinate ester. Ester hydrolysis studies conducted in human and rhesus monkey serum suggest that derivatives having an anionic solubilizing moiety (sulfonate or carboxylate) are not hydrolyzed in serum, while compounds having a cationic (tertiary amino) solubilizing moiety are hydrolyzed rapidly by serum esterases. In vivo pharmacokinetic studies in rhesus monkeys were also conducted to compare the bioconversion rates and overall bioavailability of several solution-stable prodrugs with the 21-succinate ester. Derivatives having solution stability exceeding 2 years at 25°C with a faster bioconversion rate and an overall bioavailability equal to or higher than that of the succinate ester have been identified. Relative bioavailability appears to be highly sensitive to the charge of the solubilizing pro-moiety and pro-moiety chain length.