Discovery of 2-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetic acid

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Alkylating derivatives of amino acids and peptides. Synthesis of N maleoylamino acids, [1 (N maleoyl glycyl) cysteinyl] oxytocin, and [1 (N maleoyl 11 aminoundecanoyl) cysteinyl] oxytocin. Effects on vasopressin stimulated water loss from isolated toad bladder

A method for the preparation of N maleoylamino acids and esters is reported. These compounds were shown to inhibit both the oxytocin induced smooth muscle contraction in the isolated rat uterus and the vasopressin induced water loss from the isolated toad bladder. The inhibitory ability of the maleimides in the toad bladder assay was found to be related to their corresponding partition coefficients by the equation: log 1/C = -0.055 (log P)2 + 0.227 log P + 3.96. N Maleoylamino acids can be coupled to peptides to form alkylating reagents which react rapidly with sulfhydryl groups. The synthesis of [1 (N maleoylglycyl) cysteinyl] oxytocin (3) and [1 (N maleoyl 11 aminoundecanoyl) cysteinyl] oxytocin (4) as potential affinity labeling reagents is described. These oxytocin analogs were shown to readily react with sulfhydryl containing compounds; however, neither 3 nor 4 was seen to inhibit in the rat uterus assay at concentrations up to 3×10-5 M. When tested on the mucosal and serosal surfaces of the toad bladder, assay inhibition was seen only on the mucosal surface. These results are discussed with respect to the possible existence of sulfhydryl groups at neurohypophyseal receptors.

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Discovery of an SSTR2-Targeting Maytansinoid Conjugate (PEN-221) with Potent Activity in Vitro and in Vivo

Somatostatin receptor 2 (SSTR2) is frequently overexpressed on several types of solid tumors, including neuroendocrine tumors and small-cell lung cancer. Peptide agonists of SSTR2 are rapidly internalized upon binding to the receptor and linking a toxic payload to an SSTR2 agonist is a potential method to kill SSTR2-expressing tumor cells. Herein, we describe our efforts towards an efficacious SSTR2-targeting cytotoxic conjugate; examination of different SSTR2-targeting ligands, conjugation sites, and payloads led to the discovery of 22 (PEN-221), a conjugate consisting of microtubule-targeting agent DM1 linked to the C-terminal side chain of Tyr3-octreotate. PEN-221 demonstrates in vitro activity which is both potent (IC50 = 10 nM) and receptor-dependent (IC50 shifts 90-fold upon receptor blockade). PEN-221 targets high levels of DM1 to SSTR2-expressing xenograft tumors, which has led to tumor regressions in several SSTR2-expressing xenograft mouse models. The safety and efficacy of PEN-221 is currently under evaluation in human clinical trials.

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ANTI-B7-H3 ANTIBODIES AND ANTIBODY DRUG CONJUGATES

The invention relates to B7 homology 3 protein (B7-H3) antibodies and antibody drug conjugates (ADCs), including compositions and methods of using said antibodies and ADCs.

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Sometimes chemists are able to propose two or more mechanisms that are consistent with the available data. Computed Properties of C6H5NO4, If a proposed mechanism predicts the wrong experimental rate law, however, the mechanism must be incorrect.Welcome to check out more blogs about 25021-08-3, in my other articles.

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A structurally simple minimal self-replicating system

Molecular recognition between an amidopyridine and a carboxylic acid through two complementary hydrogen bonding sites renders the reaction between an azide and a maleimide self-replicating, but not autocatalytic.

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Synthesis and study of modified polyvinyl alcohol containing amino acid moieties as anticancer agent

A series of new phthalimides compounds[3-7]a-i were synthesized from reaction of Malic anhydride, phthalic anhydride, nitro phthalic anhydride, 2-phenyl-4H-benzo[d][1,3]oxazin-4-one, 2-(4-nitrophenyl)-4H-benzo[d][1,3]oxazin-4-one with different amino acids as glycine, alanine, valine, leucine, isoleucine, serine, threonine, tyrosine and Phenyl alanine [1]a-i under fusion conditions. Compounds [3-7]a-i react with SOCl2 in the presence of benzene to produce compounds [8-12]a-i. Chemical modification of Poly(vinyl alcohol)were obtained by reaction of PVA with compounds [8-12]a-i using the dimethyl formamide to give compounds [13-17]a-i. The structure of the synthesized compounds was characterized by their analytical and spectral data as, IR spectra, 1H, 13C-NMR, Elemental analysis (CHN), UV-Vis Spectroscopy, Scanning electron microscopy (SEM), Antibacterial activity were screened via two kinds of bacteria. Also, anticancer activity were examined for most of the modified polyvinyl alcohol.

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Synthetic Transformations of Higher Terpenoids: VIII.* [4+2]-Cycloaddition Reactions of Lambertianic Acid

The Diels-Alder reaction of lambertianic acid with maleic anhydride occurred in a stereoselective fashion and yielded diastereoisomeric (1R,2S,6R,7R)- and (1S,2R,6S,7S)-exo-adducts. The latter reacted with L-valinol to give the corresponding diterpenoid imides, 4-aza-9-oxabicyclo[2.2.1]dec-8- enes. Reactions of lambertianic acid with N-substituted maleimides in the presence of Lewis acids afforded diastereoisomeric adducts having both exo and endo configuration. Some transformations of the adducts were examined with a view to obtain cantharidin and dihydroisoindole analogs.

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Synthesis of 1,8,11,12-tetrachlorotricyclo[6.2.2.02,7]dodec-2- ene-4,5:9,10-bis(dicarboximides)

1,8,11,12-Tetrachlorotricyclo[6.2.2.02,7]dodec-11-ene-4,5:9,10- bis(dicarboximides) containing similar and different substituents on the nitrogen atoms were selectively synthesized by reactions of the corresponding dianhydride and imide anhydrides with aliphatic and aromatic amines in dimethylformamide. The structure of the resulting diimides was confirmed by independent synthesis via Diels-Alder reaction of N-substituted 1,2,3,4-tetrachlorobicyclo[4.4.0]deca-2,4-diene-8,9-carboximide with substituted maleimides.

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Antibody?Drug Conjugates with Pyrrole-Based KSP Inhibitors as the Payload Class

The number of cytotoxic payload classes successfully employed in antibody?drug conjugates (ADCs) is still rather limited. The identification of ADC payloads with a novel mode of action will increase therapeutic options and potentially increase the therapeutic window. Herein, we describe the utilization of kinesin spindle protein inhibitors (KSPi) as a novel payload class providing highly potent ADCs against different targets, for instance HER-2 or TWEAKR/Fn14. Aspects of technical optimization include the development of different linker attachment sites, the stabilization of ADC linkage to avoid payload deconjugation and finally, the tailor-made design of active metabolites with a long lasting intracellular exposure in the tumor matching the mode of action of KSP inhibition. These KSPi-ADCs are highly potent and selective in vitro and demonstrate in vivo efficacy in a broad panel of tumor models including complete regressions in a patient-derived urothelial cancer model.

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Synthesis N – maleic imide-based arylalkylic and its succinyl eater of method (by machine translation)

The invention provides a method for synthesizing N – maleic imide-based arylalkylic and its succinyl eater of method, the method comprises the following steps: (a) a compound of formula (II) with 4 – nitro phenyl ester trifluoroacetic acid under the condition of the presence, in the organic solvent in the reaction of the ring occurs, the following formula (III) of the maleimido N – imino alkyl acid; and (b) of formula (III) of the maleimido N – imino alkyl acid with an acylating reagent in organic solvent, at the reflux temperature (IV) obtained by the reaction of the acyl chloride intermediate, (IV) of the acyl chloride intermediate with the N – hydroxy succinimide in the organic solvent, the presence of a base under the condition of the reaction, the following formula (V) of the N – maleic imide-based alkyl acid succinimide ester. The process is simple, high yield, and high purity of the product, is suitable for industrial production. The reaction route is as follows: (by machine translation)

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Probing selectivity in recognition-mediated dynamic covalent processes

Two simple recognition-mediated dynamic Diels-Alder systems are used to probe the role of kinetics and thermodynamics in determining the equilibrium position in exchanging libraries and the time taken to reach that equilibrium. The selectivity expressed by recognition-driven dynamic processes is demonstrated to be less than the free-energy difference between the components as a result of compensatory effects arising from the extent of conversion to products within the library.

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