Publications by authors named "Alexei Karpov"

Antibody-drug conjugates (ADCs) are an established modality that allow for targeted delivery of a potent molecule, or payload, to a desired site of action. ADCs, wherein the payload is a targeted protein degrader, are an emerging area in the field. Herein we describe our efforts of delivering a Bruton's tyrosine kinase (BTK) bifunctional degrader via a CD79b mAb (monoclonal antibody) where the degrader is linked at the ligase binding portion of the payload via a cleavable linker to the mAb.

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Targeted antimitotic agents are a promising class of anticancer therapies. Herein, we describe the development of a potent and selective antimitotic Eg5 inhibitor based antibody-drug conjugate (ADC). Preliminary studies were performed using proprietary Eg5 inhibitors which were conjugated onto a HER2-targeting antibody using maleimido caproyl valine-citrulline para-amino benzocarbamate, or MC-VC-PABC cleavable linker.

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1,3-Substituted pyrazolo[3,4-]pyridinones - were synthesized by a three-component condensation of Meldrum's acid with aryl aldehydes and 1,3-substituted 5-aminopyrazoles. Their biological activity was evaluated using the phenotypic sea urchin embryo assay and the cytotoxicity screen against human cancer cell lines. In the sea urchin embryo model, 1-benzimidazolyl-pyrazolo[3,4-]pyridinones caused inhibition of hatching and spiculogenesis at sub-micromolar concentrations.

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Herein, we report the design and synthesis of two novel bifunctional dendrons bearing multiple amine termini at the periphery and an azide at the focal point. Copper-catalyzed alkyne-azide cycloaddition enabled modular dendritic scaffold assembly resulting in a first generation dendron carrying six amines and a second generation dendron carrying eighteen amines. Peripheral amines were labeled with multiple copies of a metal isotope, whereas the azide functionality at the focal point was employed in conjugation to a single anti-human CD4 antibody.

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Antibody-drug conjugates (ADCs) are a novel modality that allows targeted delivery of potent therapeutic agents to the desired site. Herein we report our discovery of NAMPT inhibitors as a novel nonantimitotic payload for ADCs. The resulting anti-c-Kit conjugates ( and ) demonstrated efficacy in the c-Kit positive gastrointestinal stromal tumor GIST-T1 xenograft model in a target-dependent manner.

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The discovery of inhibitors targeting novel allosteric kinase sites is very challenging. Such compounds, however, once identified could offer exquisite levels of selectivity across the kinome. Herein we report our structure-based optimization strategy of a dibenzodiazepine hit 1, discovered in a fragment-based screen, yielding highly potent and selective inhibitors of PAK1 such as 2 and 3.

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Three new sterically demanding ligands based on the bispyrazolylacetic acid motif have been prepared and complexes with Fe(II), Fe(III), Ni(II) and Mn(II) have been synthesised and characterised. Single crystal X-ray structures are included for two of the ligands in the protonated form and ten other complexes. Additionally, a new general route to amide derivatives has been established, a range of amide derivatives synthesised and their coordination chemistry investigated.

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The N-donor complexing ligand 2,6-bis(5-(2,2-dimethylpropyl)-1H-pyrazol-3-yl)pyridine (C5-BPP) was synthesized and screened as an extracting agent selective for trivalent actinide cations over lanthanides. C5-BPP extracts Am(III) from up to 1 mol/L HNO(3) with a separation factor over Eu(III) of approximately 100. Due to its good performance as an extracting agent, the complexation of trivalent actinides and lanthanides with C5-BPP was studied.

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A consecutive four-component synthesis of highly-substituted tetrahydro-beta-carbolines can be achieved by a coupling-aminatio-aza-annulation-Pictet-Spengler (CAAPS) sequence creating five new sigma-bonds and four new stereocenters in a one-pot fashion. The structures were unambiguously supported by X-ray structure analyses.

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A novel sequence of Sonogashira coupling and electrophilic addition to an ynone, with concomitant deprotection and cyclocondensation, opens a new one-pot synthesis of 3-halofurans; the method can be readily elaborated to a new sequential Sonogashira-addition-cyclocondensation-Suzuki reaction to furnish 2,3,5-trisubstituted furans in a one-pot fashion.

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The four-component coupling-amination-aza-annulation-Pictet-Spengler (CAAPS) sequence of acid chlorides 1, terminal alkynes 2, tryptamine derivatives 6, and acryloyl chloride derivatives 4 represents a facile and rapid one-pot access to tetrahydro-beta-carbolines 7 in moderate to good yields.

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[reaction: see text] TMS-ynones are versatile synthetic equivalents of beta-keto aldehydes and can be readily synthesized in an atom-economical fashion by coupling (het)aroyl chlorides and (TMS)-acetylene with only one equiv (!) of triethylamine under Sonogashira conditions. This mild ynone synthesis is also a suitable entry to 2,4-disubstituted pyrimidines in the sense of a one-pot three-component reaction, i.e.

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A straightforward coupling-aminovinylation sequence of terminal alkynes 1, electron-deficient heteroaryl halides 2, and secondary amines 4 furnishes highly solvochromic push-pull chromophores 5 in good yields. Semiempirical calculations (PM3) suggest that the aminovinylation proceeds in a stepwise fashion through a zwitterionic intermediate with a final rate-determining intramolecular protonation. Crucial parameters for the success of the amine addition are the relative LUMO energies and the charge distribution at the beta-alkynyl carbon atom.

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