From Anthramycin to Pyrrolobenzodiazepine (PBD)-Containing Antibody-Drug Conjugates (ADCs).

The pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) are a family of sequence-selective DNA minor-groove binding agents that form a covalent aminal bond between their C11-position and the C2-NH2 groups of guanine bases. The first example of a PBD monomer, the natural product anthramycin, was discovered in the 1960s, and the best known PBD dimer, SJG-136 (also known as SG2000, NSC 694501 or BN2629), was synthesized in the 1990s and has recently completed Phase II clinical trials in patients with leukaemia and ovarian cancer. More recently, PBD dimer analogues are being attached to tumor-targeting antibodies to create antibody-drug conjugates (ADCs), a number of which are now in clinical trials, with many others in pre-clinical development. This Review maps the development from anthramycin to the first PBD dimers, and then to PBD-containing ADCs, and explores both structure-activity relationships (SARs) and the biology of PBDs, and the strategies for their use as payloads for ADCs.

Concise formal synthesis of porothramycins A and B via Zincke pyridinium ring-opening/ring-closing cascade.

Short formal syntheses of the antitumor antibiotics porothramycins A and B from a commercially available ester of the unnatural amino acid 3-(3-pyridyl)alanine are presented. A rearrangement cascade that presumably involves a Zincke-type pyridinium ring-opening followed by cyclization of a pendant nucleophilic amide generates the salient pyrroline ring of the alkaloids.

Synthesis and cytotoxicity on sensitive and doxorubicin-resistant cell lines of new pyrrolo[2,1-c][1,4]benzodiazepines related to anthramycin.

A new 7,8-methylenedioxy analogue (4) of (+)-porothramycin B (2) and its water-soluble sodium bisulfite derivative (15) have been synthesized in high yields and have been shown to exhibit high cytotoxic activities against several tumor cell lines. The new pyrrolo[2,1-c][1,4]benzodiazepine 4 was as effective against the resistant cell lines as against the doxorubicin-sensitive cell lines tested.

Chemical conversion of anthramycin 11-methyl ether to didehydroanhydroanthramycin and its utilization in studies of the biosynthesis and mechanism of action of anthramycin.

Reaction of anthramycin 11-methyl ether (AME) with trifluoroacetic acid results in formation of (1,11a)-didehydroanhydroanthramycin (DAA). Anthramycin biosynthetically labelled from DL-[3'RS(3'-3H)]; DL-[3'S(3'-3H)] and DL-[3'R(3'-3H)] tyrosine each lose approximately 50% of their tritium during this conversion to DAA confirming the labelling pattern of 3'-tritiated species of tyrosine in AME. As expected negligible losses of tritium occurred from AME biosynthetically labelled fron L-[2- or 6-3H] or L-[3- or 5-3H]tyrosine. DAA did not form a stable adduct with DNA in accord with the postulated mechanism of action of anthramycin.

[Research on agents with antineoplastic activity. LXIII. Anthramycin and analogous compounds. X. Synthesis of 11-phenyl-5H-pyrrolo[2,1-c] [1,4] benzodiazepine derivatives]. / Ricerche su sostanze ad attività antiblastica. Nota LXIII - Antramicina e composti analoghi. Parte X: Sintesi di derivati della 11-fenil-5H-pirrolo[2,1-c] [1,4] benzodiazepina.

Reaction between arolychlorides and 1-(2-aminobenzyl)-2-cyanopyrrole afforded the corresponding aroylamides, which were transformed by intramolecular cyclization into 11-aryl-3-cyano-5H-pyrrolo[2,1-c] [1,4] benzodiazepines. Hydrolysis of cyanoderivatives furnished the corresponding amides or acids depending on the reaction conditions. Decarboxylation and reduction of some derivatives to afford 11-aryl-5H-pyrrolo[2,1-c] [1,4] benzodiazepines and 11-aryl-3-cyano-10,11-dihydro-5H-pyrrolo[2,1-c] [1,4] benzodiazepines are described.

[Studies on substances with antiblastic activity. IX. Anthramycin and analogs. IX. Synthesis of 7-methoxy-8-hydroxy-10,11-dihydro-5H-pyrrolo[2,1-c] [1,4] benzodiazepine and other compounds related to oxotomaymycin]. / Richerche su sotanze ad attivtià antiblastica. Nota LX - Antramicina e composti analoghi. Parte IX: Sintesi della 7-metossi-8-idrossi-10,11-diidro-5H-pirrolo[2,4-c] [1,4]benzodiazepina e di altri composti correlati con la oxotomaimicina.

The synthesis of some pyrrolobenzodiazepine derivatives related to oxotomaymycin, an antibiotic recovered together with tomaymycin from fermentation broths of Streptomyces achromogenes var. tomaymycetics, is described. Reaction between 2-nitro-4-benzyloxy-5-methoxybenzylbromide and pyrrole-2-carboxyaldehyde afforded 1-(2-nitro-4-benzyloxy-5-methoxybenzyl)pyrrole-2-carboxyaldehyde. Catalytic reduction of this compound with hydrogen in the presence of Pd/C gave 10,11-dihydro-8-hydroxy-7-methoxy-5H-pyrrolo[2.1-c] [1,4]benzodiazepine. Amides obtained from condensation between 2-nitro-4-benzyloxy-5-methoxybenzoic acid chloride and proline or hydroxyproline were reduced catalytically to 2,3-dihydro-8-hydroxy-7-methoxy-1H-pyrrolo [2,1-c] [1,4]benzodiazepine-5,11 (10H, 11aH)-dione and its 2-hydroxyderivative respectively. The synthesis of 10,11-dihydro-8-hydroxy-9-methoxy-5-pyrrolo [2,1-c] [1,4]benzodiazepine is also reported.

[Study on substances with antiblastic activity. LIX - Anthramycin and analogs. VIII : synthesis of derivatives of 4H-pyrrolo/1,2-a/[1,5]benzodiazepine]. / Ricerche su sostanze ad attività antiblastica Nota LIX - Antramicina e composti analoghi. Parte VIII: Sintesi di derivati della 4H-pirrolo [1,2-a] [1,5]benzodiazepina

Preparation of 4H-pyrrolo[1,2-a][1,5]benzodiazepine derivatives related to the antitumoral antibiotic anthramycin, a derivative of 5H-pyrrolo[2,1-c] [1,4]benzodiazepine, is reported. Reaction between 1-(o-acetamidophenyl)-2-dimethylaminomethylpyrrole iodomethylate and potassium cyanide afforded 4,6-dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepine-5-one, which was then reduced to 5,6-dihydro-4H-pyrrolo[1,2-a][1,5]benzodiazepine by the action of lithium aluminum hydride. Some 6-acylderivatives of the latter compound are also described. The Vilsmeier-Haack reaction on 6-acetyl-5,6-dihydro-4H-pyrrolo[1,2-a][1,5]benzodiazepine furnished the corresponding 1-formyl derivative which was then condensed with ethyl cyanoacetate to give the related compound with the acrylic moiety.