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A self-assembled, ROS-responsive Janus-prodrug for targeted therapy of inflammatory bowel disease
A self-assembled and oxidation-degradable Janus-prodrug, termed as Bud-ATK-Tem (B-ATK-T), was fabricated by ROS-responsive aromatized thioketal (ATK) linked anti-inflammatory drug budesonide (Bud) and antioxidant tempol (Tem). Benefiting from the hydrophobic interactions and π-π stacking interactions of ATK, prodrug B-ATK-T could self-assemble into nanoparticles (NP) in water containing lecithin and DSPE-PEG2K. The morphology of B-ATK-T NP (approximate 100–120 nm) was confirmed to be regular spherical by transmission electron microscope. B-ATK-T NP was endowed high drug loading content with 41.23% for Bud and 15.55% for Tem. The rapid drug release from B-ATK-T NP proceeded in an extensive reactive oxygen species (ROS)-dependent manner. More than 98% of Bud and Tem in B-ATK-T NP could release in the mimic inflammation microenvironment or phorbol-12-myristate-13-acetate (PMA)-stimulated macrophages within short time. The release of drugs in a simultaneous and proportional manner ensures that B-ATK-T NP can increase the combined efficacy of anti-inflammation and anti-oxidation. It is worth noting that B-ATK-T NP could be passively accumulated and dramatically increasing the maximum drugs concentration in the inflamed colon of mice with inflammatory bowel disease (IBD) by oral route, and avoiding potential systemic side effects. B-ATK-T NP could not only relieve colitis via inhibiting the expression of oxidative and proinflammatory mediators more than combination of free drugs, but also significantly reduce colitis-caused death. Taken together, the self-assembled, Janus-prodrug B-ATK-T NP is a promising candidate therapies for IBD, even for other inflammatory diseases.
Li, Shanshan,Xie, Aiqing,Li, Hui,Zou, Xiang,Zhang, Qixiong
p. 66 - 78
(2019)
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FILAMENTOUS NANOSTRUCTURES AND THEIR USE FOR TREATMENT OF PULMONARY DISEASE
The present invention provides supramolecular filament and/or sphere compositions and their use as inhalable drug carriers within aerosols. The invention provides insights into peptide designs and supramolecular stability and its crucial role in the interfacial stability and aerosolization properties of the supramolecular filament and/or sphere compositions. The compositions and their properties show that molecular enrichment at the air-liquid interface during nebulization is the primary factor to deplete the monomeric peptide amphiphiles in solution, accounting for the observed morphological disruption/transitions. Importantly, encapsulation of drugs and dyes within the inventive filament and/or sphere compositions notably stabilize their supramolecular structure during nebulization, and the loaded filaments exhibit a linear release profile from a nebulizer device. The compositions disclosed herein can be used as an effective platform for the inhalation-based treatment of many lung and sinusoidal diseases.
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Paragraph 0163-0164

(2021/04/30)

Her2 targeted polypeptide drug conjugate as well as a preparation method and application thereof
The invention relates to an Her2 targeted polypeptide drug conjugate as well as a preparation method and application thereof. The Her2 targeted polypeptide drug conjugate has a molecular structural formula shown in a formula I, wherein Aaa1 is L or D type Lys or Arg; Aaa2 is L or D type Lys or Arg; X is CH2, NH or O; ROH is a hydrophobic antitumor drug; and n is 1 or 2. The Her2 targeted polypeptide drug conjugate provided by the invention can realize targeted drug delivery, the targeted polypeptide can transport the antitumor drug to specific tumor cells, the drug enters the tumor cells and then exerts the characteristic of specific degradation of disulfide bonds at tumor sites, and the antitumor drug is rapidly released. Compared with conventional joint arms such as 2,2'-dithiodiglycolicacid and 3,3'-dithiodipropionic acid, the Her2 targeted polypeptide drug conjugate provided by the invention has the advantages that an anticancer drug in the form of an original drug molecule can beobtained without further hydrolysis, the drug efficacy is improved, and the toxic and side effects on normal cells are reduced.
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Paragraph 0048; 0058-0060

(2020/05/30)

Supramolecular Design of Unsymmetric Reverse Bolaamphiphiles for Cell-Sensitive Hydrogel Degradation and Drug Release
Self-assembly of peptide-based building units into supramolecular nanostructures creates an important class of biomaterials with robust mechanical properties and improved resistance to premature degradation. Yet, upon aggregation, substrate–enzyme interactions are often compromised because of the limited access of macromolecular proteins to the peptide substrate, leading to either a reduction or loss of responsiveness to biomolecular cues. Reported here is the supramolecular design of unsymmetric reverse bolaamphiphiles (RBA) capable of exposing a matrix metalloproteinase (MMP) substrate on the surface of their filamentous assemblies. Upon addition of MMP-2, these filaments rapidly break into fragments prior to reassembling into spherical micelles. Using 3D cell culture, it is shown that drug release is commensurate with cell density, revealing more effective cell killing when more cancer cells are present. This design platform could serve as a cell-responsive therapeutic depot for local chemotherapy.
Anderson, Caleb F.,Chakroun, Rami W.,Cui, Honggang,Sneider, Alexandra,Wang, Feihu,Wirtz, Denis,Wu, Pei-Hsun
supporting information
p. 4434 - 4442
(2020/02/11)

Based on molecular glue of the fluorescence-labeled nucleotide and its use in DNA sequencing
The invention discloses a fluorescence labelled nucleotide based on a molecular glue and a use thereof in DNA sequencing. The structure formula of the fluorescence labelled nucleotide is shown in a formula (I) in the specification, wherein R1 is shown in the specification, R2 is fluorescein or shown in the specification, and dNTP is ribonucleoside triphosphote which contains four different base groups; the fluorescein is selected from one of the BODIPY, rhodamine, coumarin, xanthene, cyanin, pyrene, phthalocyanine, alexa, a squarene dye, a composition for generating energy transfer dye and the derivatives thereof. The fluorescence labelled nucleotide can be used for DNA sequencing; simultaneously the raw materials for synthesizing the fluorescence labelled nucleotide are simple and easy to obtain and the fluorescence labelled nucleotide can be used for large-scale popularization. The biological assessment result shows that all the requirements of the high-throughput sequencing biochemical reaction can be satisfied by the reversible terminal, and the reversible terminal has good practical prospect.
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Paragraph 0102; 0104

(2018/01/05)

Structure-activity relationships of small molecule autotaxin inhibitors with a discrete binding mode
Autotaxin (ATX) is a secreted enzyme responsible for the hydrolysis of lysophosphatidylcholine (LPC) to the bioactive lysophosphatidic acid (LPA) and choline. The ATX-LPA signaling pathway is implicated in cell survival, migration, and proliferation; thus, the inhibition of ATX is a recognized therapeutic target for a number of diseases including fibrotic diseases, cancer, and inflammation, among others. Many of the developed synthetic inhibitors for ATX have resembled the lipid chemotype of the native ligand; however, a small number of inhibitors have been described that deviate from this common scaffold. Herein, we report the structure-activity relationships (SAR) of a previously reported small molecule ATX inhibitor. We show through enzyme kinetics studies that analogues of this chemotype are noncompetitive inhibitors, and by using a crystal structure with ATX we confirm the discrete binding mode.
Miller, Lisa M.,Keune, Willem-Jan,Castagna, Diana,Young, Louise C.,Duffy, Emma L.,Potjewyd, Frances,Salgado-Polo, Fernando,García, Paloma Engel,Semaan, Dima,Pritchard, John M.,Perrakis, Anastassis,MacDonald, Simon J. F.,Jamieson, Craig,Watson, Allan J. B.
p. 722 - 748
(2017/02/05)

Molecular design and synthesis of self-assembling camptothecin drug amphiphiles
The conjugation of small molecular hydrophobic anticancer drugs onto a short peptide with overall hydrophilicity to create self-assembling drug amphiphiles offers a new prodrug strategy, producing well-defined, discrete nanostructures with a high and quantitative drug loading. Here we show the detailed synthesis procedure and how the molecular structure can influence the synthesis of the self-assembling prodrugs and the physicochemical properties of their assemblies. A series of camptothecin-based drug amphiphiles were synthesized via combined solid- and solution-phase synthetic techniques, and the physicochemical properties of their self-assembled nanostructures were probed using a number of imaging and spectroscopic techniques. We found that the number of incorporated drug molecules strongly influences the rate at which the drug amphiphiles are formed, exerting a steric hindrance toward any additional drugs to be conjugated and necessitating extended reaction time. The choice of peptide sequence was found to affect the solubility of the conjugates and, by extension, the critical aggregation concentration and contour length of the filamentous nanostructures formed. In the design of self-assembling drug amphiphiles, the number of conjugated drug molecules and the choice of peptide sequence have significant effects on the nanostructures formed. These observations may allow the fine-tuning of the physicochemical properties for specific drug delivery applications, ie systemic vs local delivery.
Cheetham, Andrew G.,Lin, Yi-An,Lin, Ran,Cui, Honggang
p. 874 - 884
(2017/06/09)

Redox-responsive flower-like micelles of poly(l-lactic acid)-b-poly(ethylene glycol)-b-poly(l-lactic acid) for intracellular drug delivery
Redox-responsive micelles self-assembled from triblock copolymers of poly(l-lactic acid)-poly(ethylene glycol)-poly(l-lactic acid) (PLA-PEG-PLA) with double-disulfide linkage in the backbone were synthesized and characterized by proton nuclear magnetic resonance (1H NMR) and size exclusion chromatography (SEC), in which both PEG (Mn = 1000, 2000 and 4000 g mol-1) and PLA (Mn = 1600 g mol-1) have different molecular weights respectively. The triblock copolymers PLA3000-PEG2000-PLA3000 and PLA3000-PEG4000-PLA3000 can self-assemble into flower-like micelles in aqueous media with average diameters 110 nm and 43 nm and lower critical micelle concentrations (CMC) 0.017 and 0.014 mg mL-1 respectively compared with that of diblock copolymers. Moreover, in vitro drug release analyses indicated that reductive environment can result in triggered drug release profiles. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl- 2-H-tetrazolium bromide (MTT) assay in vitro showed no significant cytotoxicity as NIH 3T3 cells incubated in the micelles even when the concentrations up to 1000 μg/mL. Additionally fluorescence microscopy measurements and MTT assay demonstrated that the micelles exhibited a faster drug release and higher cellular proliferation inhibition due to the effect of intracellular reduction responsiveness compared with that of diblock copolymers. The above results suggest that the reduction-responsive, biodegradable and biocompatibility micelles could provide a platform to construct potential drug delivery systems for cancer therapy.
Yang, Qinglai,He, Changyu,Zhang, Zhen,Tan, Lianjiang,Liu, Bingya,Zhu, Zhenggang,Shao, Zhifeng,Gong, Bing,Shen, Yu-Mei
p. 351 - 362
(2016/04/05)

Dynamic covalent diblock copolymers: Instructed coupling, micellation and redox responsiveness
Instructed by association units that allow reversible and unsymmetrical disulfide bond formation, hydrophilic (PEG) and hydrophobic (PLA) polymer chains are efficiently coupled into amphiphilic diblock copolymers. The desymmetrization of otherwise symmetrical reversible disulfide bond formation is achieved with amide association units that integrate both directional H-bonding and reversible disulfide bond formation, which ensure the connection of different polymer blocks while minimizing self-coupling. The resultant amphiphilic block copolymers self-assemble into long-lasting spherical micelles that are responsive to free thiols.
Yang, Qinglai,Bai, Ling,Zhang, Yuanqing,Zhu, Fangxia,Xu, Yuhong,Shao, Zhifeng,Shen, Yu-Mei,Gong, Bing
p. 7431 - 7441
(2015/01/08)

NOVEL SELF-ASSEMBLING DRUG AMPHIPHILES AND METHODS FOR SYNTHESIS AND USE
The present invention provides herein the design of monodisperse, amphiphilic anticancer drugs—which are now termed “drug amphiphiles” (DAs)—that can spontaneously associate into discrete, stable supramolecular nanostructures with the potential for self-delivery (no additional carriers are needed). The quantitative drug loading in the resulting nanostructures is ensured by the very nature of the molecular design. The DA is a composition comprising: D-L-PEP; wherein D is 1 to 4 hydrophobic drug molecules which can be the same or different; L is 1 to 4 biodegradable linkers which can be the same or different; and PEP is a peptide that can spontaneously associate into discrete, stable supramolecular nanostructures. In an alternate embodiment, the DA composition also comprises a targeting ligand (T). Methods of making DA molecules, as well as their use in treatment of disease are also provided.
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Paragraph 0114

(2014/05/07)

Linker-determined drug release mechanism of free camptothecin from self-assembling drug amphiphiles
We report here that the release mechanism of free camptothecin from self-assembling drug amphiphiles can be regulated by use of different linker groups. Our results highlight the significance of the linker group of drug amphiphiles on the drug release efficiency and their consequent in vitro efficacy. the Partner Organisations 2014.
Cheetham, Andrew G.,Ou, Yu-Chuan,Zhang, Pengcheng,Cui, Honggang
supporting information
p. 6039 - 6042
(2014/05/20)

METHODS FOR THE PREPARATION OF CHARGED CROSSLINKERS
Processes for the preparation of charged crosslinkers bearing a sulfonic acid moiety are disclosed. These procedures also optionally include methods to convert the resulting products to substantially a single salt form.
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Page/Page column 3

(2012/06/30)

Structure-activity study of new inhibitors of human betaine-homocysteine S-methyltransferase
Betaine-homocysteine S-methyltransferase (BHMT) catalyzes the transfer of a methyl group from betaine to L-homocysteine, yielding dimethylglycine and L-methionine. In this study, we prepared a new series of BHMT inhibitors. The inhibitors were designed to mimic the hypothetical transition state of BHMT substrates and consisted of analogues with NH, N(CH3), or N(CH 3)2 groups separated from the homocysteine sulfur atom by a methylene, ethylene, or a propylene spacer. Only the inhibitor with the N(CH3) moiety and ethylene spacer gave moderate inhibition. This result led us to prepare two inhibitors lacking a nitrogen atom in the S-linked alkyl chain: (RS,RS)-5-(3-amino-3-carboxypropylthio)-3-methylpentanoic acid and (RS)-5-(3-amino-3-carboxypropylthio)-3,3-dimethylpentanoic acid. Both of these compounds were highly potent inhibitors of BHMT. The finding that BHMT does not tolerate a true betaine mimic within these inhibitors, especially the nitrogen atom, is surprising and evokes questions about putative conformational changes of BHMT upon the binding of the substrates/products and inhibitors.
Vaněk, Václav,Budě?ínsky, Milo?,Kabeleová, Petra,?anda, Miloslav,Koz?í?ek, Milan,Han?lová, Ivona,Mládková, Jana,Brynda, Ji?í,Rosenberg, Ivan,Koutmos, Markos,Garrow, Timothy A.,Jirá?ek, Ji?í
experimental part
p. 3652 - 3665
(2010/04/30)

Sequence-specific association in aqueous media by integrating hydrogen bonding and dynamic covalent interactions
Oligoamide strands that associate in a sequence-specific fashion into hydrogen-bonded duplexes in nonpolar solvents were converted into disulfide cross-linked duplexes in aqueous media. Thus, by incorporating trityl-protected thiol groups, which allows the reversible formation of disulfide bonds, into the oligoamide strands, only duplexes consisting of complementary hydrogen-bonding sequences were formed in aqueous solution as well as in methanol. The sequence-specific cross-linking of oligoamide strands was confirmed by MALDI-TOF, reverse-phase HPLC, and by isolating a cross-linked duplex. This study demonstrates that the sequence-specificity characteristic of multiply hydrogen-bonded systems can be extended into competitive media through the interplay of H-bonding and reversible covalent interactions, based on which a new class of molecular associating and ligating units that are compatible with both polar and nonpolar environments can be conveniently obtained. Copyright
Li, Minfeng,Yamato, Kazuhiro,Ferguson, Joseph S.,Gong, Bing
p. 12628 - 12629
(2008/02/05)

Cross-linkers with high reactivity and solubility and their use in the preparation of conjugates for targeted delivery of small molecule drugs
Disclosed is a method of making conjugates of cell binding agents and small molecule drugs comprising reacting a cell binding agent with a bifunctional cross-linking moiety to thereby provide the cell binding agent with a reactive disulfide group and then reacting the modified cell binding agent with a small molecule drug comprising a free thiol group. Bifunctional cross-linking moieties are also disclosed.
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(2008/06/13)

S-4-Methoxytrityl mercapto acids: Synthesis and application
4-Methoxytrityl (Mmt)-mercapto acids were obtained either by the reaction of mercapto acids with Mmt-chloride or by the reaction of halo acids with Mmt-thiol. The derivatives obtained were used in the solid-phase synthesis of small libraries of mercaptoacylamino acids and mercaptoacyl peptides. The removal of the Mmt-group was performed by treatment with trifluoroacetic acid (TFA) in dichloromethane (DCM) using triethylsilane (TES) as scavenger.
Mourtas, Spyros,Gatos, Dimitrios,Kalaitzi, Vagiani,Katakalou, Christina,Barlos, Kleomenis
p. 6965 - 6967
(2007/10/03)

Leukotriene antagonistic benzoic acid derivatives
The invention relates to benzoic acid derivatives being leukotriene antagonists. The compounds therefore are suitable as active ingredients in medicaments particularly in medicaments for the treatment of respiratory diseases.
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(2008/06/13)

Probing the activities and mechanisms of leukotriene A4 hydrolase with synthetic inhibitors
Leukotriene (LT) A4 hydrolase catalyzes the hydrolysis of leukotriene A4 to form leukotriene B4, a potent inflammatory mediator. Recently, the synthesis and evaluation of the highly effective competitive LTA4 hydrolase inhibitor 2 (K(i) = 1.6 nM) was described. In the present study, we describe the biological activity of 2 against LTB4 biosynthesis, as well as the design, synthesis, and evaluation of a new series of inhibitors intended to probe the active site of the enzyme. On the basis of these results and of previously reported site-directed mutagenesis and inhibition studies, the mechanisms of peptide and epoxide hydrolysis catalyzed by LTA4 hydrolase are discussed.
Hogg, J. Heather,Ollmann, Ian R.,Wetterholm, Anders,Andberg, Martina Blomster,Haeggstroem, Jesper,Samuelsson, Bengt,Wong, Chi-Huey
p. 1698 - 1713
(2007/10/03)

HIGHLY CHEMO-,REGIO-,and STEREOSELECTIVE INTRODUCTION OF A CIS-DOUBLE BOND INTO A THIA-ANALOGUE OF STEARIC ACID
Replacement of a methylene group by a sulfur atom at the 5-position of stearic acid does not prevent the introduction of a cis-double bond at the 9-,10-positions.
Buist, Peter H.,Dallmann, Garry H.,Rymerson, Robert T.,Siegel, Peter M.
p. 857 - 860
(2007/10/02)

Quinoxaline bleach catalysts
Quinoxalines of the formula STR1 are provided, in which R1 is hydrogen if R3 and R4 conjointly are --O(CH2)p O--, or is --CH2 OR, --CH2 NRR', --CH2 OCOR, --CH2 Cl, --CH2 Br, --CH2 CN, --CH2 SR, --CH2 SCN, --CH2 O(CH2)m OR, --CH2 (OCH2 CH2)n OR, --CH2 SO2 R5, --CH2 PO(OR5)2, --CH2 SO3 R6 or --CH2 PO(OR6)2 and R2 is lower alkyl, --CH2 PO(OR5)2, --CH2 PO(OR6)2 or CH2 SO3 R6, R3 and R4 independently are lower alkyl, lower alkoxy, RO(CH2)m O-- or RO(CH2 CH2 O)n -- or R3 and R4 conjointly are --O(CH2)p O--, R and R' independently are hydrogen or lower alkyl, R5 is lower alkyl, R6 is hydrogen, an alkali metal cation or --N≈ (R)4, m is 3 or 4, n is 1 to 3 and p is 1 or 2. The quinoxalines are useful as bleach catalysts, especially as dye bleach catalysts, in processing baths for the photographic silver dye bleach process.
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(2008/06/13)

Azole derivatives
Azole derivatives of the formula SPC1 Wherein R1 is free or esterified carboxyl or other functionally modified carboxyl group, R2 and R3 each are aryl; A is Cn H2n in which n is an integer from 1 to 10, inclusive; and Z is O or S; and the physiologically acceptable salts thereof, possess, with good compatibility, excellent antiphlogistic activity and, in particular, influence favorably the chronic progressive diseases of the joints, e.g., arthritis. They can be prepared from compounds of the formula SPC2 Wherein X1 is a group convertible into the group --S--A--R1, and R2 and R3 have the values given above.
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(2008/06/13)