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1.	Hartmann, Rafael, et al. (författare) Rational Design of Azastatin as a Potential ADC Payload with Reduced Bystander Killing. 2020 Ingår i: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 15:24, s. 2500-2512 Tidskriftsartikel (refereegranskat)abstract Auristatins are a class of ultrapotent microtubule inhibitors, whose growing clinical popularity in oncology is based upon their use as payloads in antibody-drug conjugates (ADCs). The most widely utilized auristatin, MMAE, has however been shown to cause apoptosis in non-pathological cells proximal to the tumour ("bystander killing"). Herein, we introduce azastatins, a new class of auristatin derivatives encompassing a side chain amine for antibody conjugation. The synthesis of Cbz-azastatin methyl ester, which included the C2-elongation and diastereoselective reduction of two proteinogenic amino acids as key transformations, was accomplished in 22 steps and 0.76 % overall yield. While Cbz-protected azastatin methyl ester (0.13-3.0 nM) inhibited proliferation more potently than MMAE (0.47-6.5 nM), removal of the Cbz-group yielded dramatically increased IC50 -values (9.8-170 nM). We attribute the reduced apparent cytotoxicity of the deprotected azastatin methyl esters to a lack of membrane permeability. These results clearly establish the azastatins as a novel class of cytotoxic payloads ideally suited for use in next-generation ADC development.

Hartmann, Rafael, et al. (författare)
Rational Design of Azastatin as a Potential ADC Payload with Reduced Bystander Killing.
2020
Ingår i: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 15:24, s. 2500-2512
Tidskriftsartikel (refereegranskat)abstract
- Auristatins are a class of ultrapotent microtubule inhibitors, whose growing clinical popularity in oncology is based upon their use as payloads in antibody-drug conjugates (ADCs). The most widely utilized auristatin, MMAE, has however been shown to cause apoptosis in non-pathological cells proximal to the tumour ("bystander killing"). Herein, we introduce azastatins, a new class of auristatin derivatives encompassing a side chain amine for antibody conjugation. The synthesis of Cbz-azastatin methyl ester, which included the C2-elongation and diastereoselective reduction of two proteinogenic amino acids as key transformations, was accomplished in 22 steps and 0.76 % overall yield. While Cbz-protected azastatin methyl ester (0.13-3.0 nM) inhibited proliferation more potently than MMAE (0.47-6.5 nM), removal of the Cbz-group yielded dramatically increased IC50 -values (9.8-170 nM). We attribute the reduced apparent cytotoxicity of the deprotected azastatin methyl esters to a lack of membrane permeability. These results clearly establish the azastatins as a novel class of cytotoxic payloads ideally suited for use in next-generation ADC development.

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