145325-48-0

Upstream product

• 628-77-3 1,5-diiodopentane 
• 121-34-6 3-methoxy-4-hydroxybenzoic acid 
• 111-24-0 1,5-dibromo-pentane 
• 145325-42-4 1',5'-bis<2-methoxy-(4-methoxycarbonyl)phenoxy>pentane 
• 111-29-5 1 ,5-pentanediol 
• 3943-74-6 4-hydroxy-3-methoxybenzoic acid methyl ester 
• 145325-45-7 1',5'-bis[2-methoxy-4-(methoxycarbonyl)-5-nitrophenoxy]pentane 

Downstream Products

• 260418-26-6 1,1'-[[(pentane-1,5-diyl)dioxy]-bis[(2-amino-5-methoxy-1,4-phenylene)carbonyl]]-bis[(2S,4R)-2-t-butyldimethylsilyloxymethyl-4-hydroxypyrrolidine] 
• 260418-30-2 1,1'-[[(pentane-1,5-diyl)dioxy]-bis[(2-amino-N-allyloxycarbonyl-5-methoxy-1,4-phenylene)carbonyl]]-bis[(2S)-2-hydroxymethyl-4-methylidene-2,3-dihydropyrrole] 
• 260418-25-5 (S,R)-((pentane-1,5-diylbis(oxy))bis(5-methoxy-2-nitro-4,1-phenylene))bis(((2S,4R)-2-(((tert-butyldimethylsllyl)oxy)methyl)-4-hydroxypyrrolidin-1-yl) methanone) 
• 260418-28-8 1,1'-[[(pentane-1,5-diyl)dioxy]-bis[(2-amino-N-allyloxycarbonyl-5-methoxy-1,4-phenylene)carbonyl]]-bis[(2S)-2-t-butyldimethylsilyloxymethyl-4-oxo-pyrrolidine] 
• 260418-27-7 1,1'-[[(pentane-1,5-diyl)dioxy]-bis[(2-amino-N-allyloxycarbonyl-5-methoxy-1,4-phenylene)carbonyl]]-bis[(2S,4R)-2-t-butyldimethylsilyloxymethyl-4-hydroxypyrrolidine] 
• 260418-29-9 1,1'-[[(pentane-1,5-diyl)dioxy]-bis[(2-amino-N-allyloxycarbonyl-5-methoxy-1,4-phenylene)carbonyl]]-bis[(2S)-2-t-butyldimethylsilyloxymethyl-4-methylidene-2,3-dihydropyrrole] 
• 848004-66-0 (S)-((pentane-1,5-diylbis(oxy))bis(5-methoxy-2-nitro-4,1-phenylene))bis(((S)-2-(hydroxymethyl)pyrrolidin-1-yl)methanone) 
• 913262-32-5 1,1'-[[(pentane-1,5-diyl)dioxy]bis[(2S,4R)-[5-methoxy-1,4-phenylene-2-(2,2,2-trichloroethoxycarbonylamino)]carbonyl]]bis[2-(tert-butyldimethylsilyloxymethyl)-4-hydroxyacetylpyrrolidine] 
• 913262-33-6 1,1'-[[(pentane-1,5-diyl)dioxy]bis[(2S,4R)-[5-methoxy-1,4-phenylene-2-(2,2,2-trichloroethoxycarbonylamino)]carbonyl]]bis[2-hydroxymethyl-4-hydroxyacetylpyrrolidine] 
• 913262-30-3 1,1'-[[(pentane-1,5-diyl)dioxy]bis[(2S,4R)-(5-methoxy-2-nitro-1,4-phenylene)carbonyl]]bis[2-(tert-butyldimethylsilyloxymethyl)-4-hydroxyacetylpyrrolidine] 
• 913262-31-4 1,1'-[[(pentane-1,5-diyl)dioxy]bis[(2S,4R)-(5-methoxy-2-amino-1,4-phenylene)carbonyl]]bis[2-(tert-butyldimethylsilyloxymethyl)-4-hydroxyacetylpyrrolidine] 
• 1343476-08-3 (S)-(4,4‘-(pentane-1,5-diylbis(oxy))bis(5-methoxy-2-nitro-4,1-phenylene))bis(((S)-2-(methoxycarbonyl)-4-methylenepyrrolidin-1-yl)methanone) 

Relevant academic research and scientific papers

Design and synthesis of a folate-receptor targeted diazepine-ring-opened pyrrolobenzodiazepine prodrug conjugate

Pyrrolobenzodiazepines (PBDs) and their dimers (bis-PBDs) have emerged as some of the most potent chemotherapeutic compounds and are currently under development as novel payloads in antibody-drug conjugates (ADCs). However, when used as stand-alone therapeutics or as warheads for small molecule drug conjugates (SMDCs), dose-limiting toxicities are often observed. As an elegant solution to this inherent problem, we designed and synthesized a diazepine-ring-opened bis-PBD prodrug (pro-PBD-PBD) folate conjugate lacking the one of the two imine moieties found in the corresponding free bis-PBD. Upon entering a targeted cell, cleavage of the linker system, including the hydrolysis of an oxazolidine moiety, results in the formation of a reactive intermediate which possesses a newly formed aldehyde as well as an aromatic amine. A fast and spontaneous intramolecular ring-closing reaction subsequently takes place as the aromatic amine adds to the aldehyde with the loss of water to give the imine, and as a result, the diazepine ring, thereby delivering the bis-PBD to the targeted cell. The in vitro and in vivo activity of this conjugate has been evaluated on folate receptor positive KB cells. Sub-nanomolar activity with good specificity and high cure rates with minimal toxicity have been observed.

CROSS-LINKED PYRROLOBENZODIAZEPINE DIMER (PBD) DERIVATIVE AND ITS CONJUGATES

A novel cross-linked cytotoxic agents, pyrrolobenzo-diazepine dimer (PBD) derivatives, and their conjugates to a cell-binding molecule, a method for preparation of the conjugates and the therapeutic use of the conjugates.

CONJUGATION LINKERS CONTAINING 2,3-DIAMINOSUCCINYL GROUP

Provided is a conjugate of a cytotoxic drug/molecule to a cell-binding molecule with a bis-linker (adual-linker) containing a 2, 3-diaminosuccinyl group. It also relates to preparation of the conjugate of a cytotoxic drug/molecule to a cell-binding molecule with the bis-linker, particularly when the drug having functional groups of amino, hydroxyl, diamino, amino-hydroxyl, dihydroxyl, carboxyl, hydrazine, aldehyde and thiol for conjugation with the bis-linker in a specific manner, as well as the therapeutic use of the conjugates.

PBD CONJUGATES FOR TREATING DISEASES

The present disclosure relates to pyrrolobenzodiazepine (PBD) prodrugs and conjugates thereof. The present disclosure also relates to pharmaceutical compositions of the conjugates described herein, methods of making and methods of using the same.

Latent Warheads for Targeted Cancer Therapy: Design and Synthesis of pro-Pyrrolobenzodiazepines and Conjugates

Pyrrolobenzodiazepines (PBDs) and their dimers (bis-PBDs) have emerged as some of the most potent chemotherapeutic compounds, and are currently under development as novel payloads in antibody-drug conjugates (ADCs). However, when used as stand-alone thera

CONJUGATES FOR TREATING DISEASES

The present disclosure relates to pyrrolobenzodiazepine (PBD) prodrugs and conjugates thereof. The present disclosure also relates to pharmaceutical compositions of the conjugates described herein, methods of making and methods of using the same.

Linker Length Modulates DNA Cross-Linking Reactivity and Cytotoxic Potency of C8/C8′ Ether-Linked C2-exo-Unsaturated Pyrrolo[2,1-c][1,4]benzodiazepine (PBD) Dimers

A C2/C2′-exo-unsaturated pyrrolo[2,1-c][1,4]benzodiazepine (PBD) dimer 4b (DRG-16) with a C8-O(CH2)nO-C8′ diether linkage (n = 5) has been synthesized that shows markedly superior in vitro cytotoxic potency (e.g., > 3400-fold in IGRO

Pyrrolobenzodiazepines

Compounds of the formulae Ia and Ib: wherein: A is CH2, or a single bond; R2 is selected from: R, OH, OR, CO2H, CO2R, COH, COR, SO2R, CN; R6, R7 and R9 are independently selected from H, R, OH, OR, halo, amino, NHR, nitro, Me3Sn; and R8 is selected from H, R, OH, OR, halo, amino, NHR, nitro, Me3Sn, where R is as defined above, or the compound is a dimer with each monomer being the same or different and being of formula Ia or Ib, where the R8 groups of the monomers form together a bridge having the formula —X—R′—X— linking the monomers, where R′ is an alkylene chain containing from 3 to 12 carbon atoms, which chain may be interrupted by one or more hetero-atoms and/or aromatic rings and may contain one or more carbon-carbon double or triple bonds, and each X is independently selected from O, S, or N; except that in a compound of formula Ia when A is a single bond, then R2 is not CH═CH(CONH2) or CH═CH(CONMe2). Other related compounds are also disclosed.

Pyrrolobenzodiazepines

Compounds of the formulae Ia and Ib: wherein:A is CH2, or a single bond;R2 is selected from: R, OH, OR, CO2H, CO2R, COH, COR, SO2R, CN;R6, R7 and R9 are independently selected from H, R, OH, OR, halo, amino, NHR, nitro, Me3Sn;and R8 is selected from H, R, OH, OR, halo, amino, NHR, nitro, Me3Sn, where R is as defined above, or the compound is a dimer with each monomer being the same or different and being of formula Ia or Ib, where the R8 groups of the monomers form together a bridge having the formula -X-R'-X- linking the monomers, where R' is an alkylene chain containing from 3 to 12 carbon atoms, which chain may be interrupted by one or more hetero-atoms and/or aromatic rings and may contain one or more carbon-carbon double or triple bonds, and each X is independently selected from O, S, or N; except that in a compound of formula Ia when A is a single bond, then R2 is not CH=CH(CONH2) or CH=CH(CONMe2). Other related compounds are also disclosed.

Synthesis of sequence-selective C8-linked pyrrolo[2,1-c][1,4]benzodiazepine DNA interstrand cross-linking agents

An efficient convergent synthesis of a homologous series of C8-linked pyrrolobenzodiazepine dimers with remarkable DNA interstrand cross-linking activity and potent in vitro cytotoxicity is reported. The 'amino thioacetal' cyclization procedure was used t