Nemorubicin

Abstract

Nemorubicin is a 3'-deamino-3'[2-(S)-methoxy-4-morpholinyl]derivative of doxorubicin. This derivative has been synthesized in the early 1990s by the Farmitalia CarloErba Research Center in Italy. The idea was to develop doxorubicin analogues able to circumvent the emergenceof chemoresistance, in particular the multi-drug resistance. The drug was reported to be active in vitroagainst both murine and human tumor cells resistant to doxorubicin. Similar results were obtained whenthe drug was administered in vivo to mice bearing multi-drug resistant tumors. The compound retained thesame activity also in alkylating agents and topoisomerase II resistant tumors and showed an increased potencyrelative to the parent drug doxorubicin. It is metabolized via P450 CYP3A enzyme to an extremely cytotoxicderivative. Both nemorubicin and its metabolite have a mechanism of action different from that ofdoxorubicin, with a key role played by the nucleotide excision repair system. The drug is activelytested in clinics as a single agent or in combination with cisplatin.

Computational Chemogenomics Drug Repositioning Strategy Enables the Discovery of Epirubicin as a New Repurposed Hit for Plasmodium falciparum and P. vivax

“…Conformational studies support the fact that daunosamine presents the most spatial flexibility among the anthracycline domains ( 71 ), tolerating modulation of its properties via sugar modifications ( 69 ). Examples of doxorubicin optimization have led to the development of expanded-spectrum anthracyclines like nemorubicin ( 72 , 73 ) and sabarubicin ( 74 ), which are less cardiotoxic drugs. Based on these observations, we suggest alterations within the sugar moiety of epirubicin aiming to reduce its toxicity and generate compounds with improved pharmacological and pharmacokinetics profiles.…”

A non-internalizing antibody-drug conjugate based on an anthracycline payload displays potent therapeutic activity in vivo

“…PNU159682 has emerged as a potent anthracycline derivative, with cytotoxic activity in the picomolar concentration range 16. This compound was identified as the most active product of metabolic conversion of Nemorubicin, carried out by the CYP3A4 enzyme 17. Recently, PNU159682 was coupled to an internalizing anti-CD22 antibody: the resulting conjugate was administered to mice xenografted with cancer cell lines resistant to MMAE-bearing ADC analogues, exhibiting a significant antitumor effect 18.…”

Antitumour Anthracyclines: Progress and Perspectives

“…In the preclinical phase, it was intensely potent, active against drug‐resistant P388 and LoVo cell lines and MX‐1 mammary tumour xenografts, and not cardiotoxic. It is believed to be bioconverted by P450 CYP3 A into active metabolites to induce DNA strand breaks primarily through topoisomerase I cleavage …”