120205-58-5

Upstream product

• 135383-56-1 (3R,4S,5S)-4--3-methoxy-5-methylheptanoic acid 
• 115-11-7 isobutene 
• 333-27-7 methyl trifluoromethanesulfonate 
• 120294-43-1 tert-Butyl (3R,4S,5S)-3-hydroxy-4--5-methylheptanoate 
• 420-37-1 trimethoxonium tetrafluoroborate 
• 135383-54-9 (4S,5S)-4-Benzyloxycarbonylamino-5-methyl-3-oxo-heptanoic acid tert-butyl ester 
• 150942-98-6 t-butyl lithioacetate 
• 3160-59-6 N-Cbz-L-Isoleucine 
• 149664-79-9 (3R,4S,5S)-4-(Benzyloxycarbonyl-methyl-amino)-3-methoxy-5-methyl-heptanoic acid methyl ester 
• 135383-55-0 (3R,4S,5S)-4-Benzyloxycarbonylamino-3-hydroxy-5-methyl-heptanoic acid tert-butyl ester 
• 120205-56-3 benzyl methyl[(2S,3S)-3-methyl-1-oxopentan-2-yl]carbamate 
• 42417-66-3 (2S,3S)-3-methyl-2-(methyl{[(phenylmethyl)oxy]carbonyl}amino)pentanoic acid 
• 120205-55-2 benzyl [(2S,3S)-1-hydroxy-3-methylpentan-2-yl]methylcarbamate 

Downstream Products

• 159173-45-2 (3R,4S,5S)-Dil-(2R,3R,4S)-Dap-(S)-Doe 
• 135383-61-8 Cbz-Dil-Dap-Doe 
• 135383-62-9 Boc-(S)-Val-(3R,4S,5S)-Dil-(2R,3R,4S)-Dap-(S)-Doe 
• 120205-48-3 tert-Butyl (3R,4S,5S)-3-methoxy-4-(N-methylamino)-5-methylheptanoate hydrochloride 
• 1438852-21-1 methyl (S)-2-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-N,3-dimethylbutanamido)-3-methoxy-5-methylheptanoyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropanamido)-3-phenylpropanoate 
• 1438852-80-2 pentafluorophenyl (3R,4S,5S)-4-[{N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-valyl}(methyl)amino]-3-methoxy-5-methylheptanoate 

Relevant academic research and scientific papers

Rational Design of Azastatin as a Potential ADC Payload with Reduced Bystander Killing

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.

CYTOTOXIC PEPTIDES AND ANTIBODY DRUG CONJUGATES THEREOF

The present invention is directed to cytotoxic pentapeptides, to antibody drug conjugates thereof, and to methods for using the same to treat cancer.

CYTOTOXIC PEPTIDES AND ANTIBODY DRUG CONJUGATES THEREOF

The present invention is directed to cytotoxic pentapeptides, to antibody drug conjugates thereof, and to methods for using the same to treat cancer.

Dolastatins 23: Stereospecific synthesis of dolaisoleuine

The remarkable antineoplastic peptide dolastatin 10, isolated from the opisthobranchia mollusc Dolabella auricularia, is currently in clinical development and further improvements in its total synthesis have been undertaken. Major effort has been directed at devising more stereoselective routes to the dolastatin 10 amino acid units dolaisoleuine 2 and dolaproine 3, each bearing three chiral centres. We report herein highly stereoselective routes to both natural (3R,4S,5S)-dolaisoleuine 2 and its 3S,4S,5S-isomer 14 (Z replaces H) using an asymmetric aldol methodology. Key reaction steps are condensation of chiral α-(methylsulfanyl)acetyloxazolidinone 4d with (S)-N-Z-N-Me-isoleucinal 6 using dibutylboron triflate followed by reductive desulfurization, O-methylation and cleavage of the oxazolidinone auxiliary to complete a simple route to N-benzyloxycarbonyldolaisoleuine 10. By substituting chiral oxazolidinone 5d for 4d the 3S-isomer of N-benzyloxycarbonyldolaisoleuine 14 was selectively obtained.

Synthesis and antitumor activity of novel dolastatin 10 analogs

Dolastatin 10 (1) is a potent antineoplastic pentapeptide. Novel dolastatin 10 analogs each modified at one of the constituent amino acid derivatives, were synthesized and their antitumor activity was evaluated against P388 leukemia in mice. The structural requirements for antitumor activity are discussed. Some of the analogs, 31c, 35c, 38b, and 50c showed excellent activity in vivo. Highly active 50c, which lacks the thiazole group of 1, was selected for further development as an antitumor agent.

The dolastatins. 19. Synthesis of dolaisoleuine

The synthesis of dolaisoleuine as its tert-butyl ester (Dil-OBu(t)), a β- methoxy-γ-amino acid component of dolastatin 10, has been achieved employing as key step an aldol condensation between N-(benzyloxycarbonyl)-N-methyl- (S,S)-isoleucinal and tert-butyl acetate followed by O-methylation. The overall six-step reaction sequence to Dil proved to be convenient for routine preparation of this new amino acid and its stereochemical assignment as (3R,4S,5S)-N,O-dimethylisostatine.

An expeditious synthesis of dolastatin 10

Total synthesis of dolastatin 10 (1) was completed by developing an efficient synthesis of two key amino acid components, Dil (6) and Dap (11), and subsequent stepwise coupling of five amino acid components from C-terminal Doe.