CC-1065 and the duocarmycins: recent developments

Abstract

It is accepted that neoplastic diseases are related to gene alteration or oncogene activation. In particular, DNA minor groove binding drugs have been extensively studied through the years in order to influence the regulation of gene expression by means of specific interactions with DNA based moieties. In this field, analogues of naturally occurring antitumour agents, such as CC-1065 and/or the duocarmycins, represent a new class of highly potent antineoplastic compounds, currently under investigation. CC-1065 and duocarmycins represent a class of exceptionally potent antitumour antibiotics that derive their biological effects from the reversible, stereoelectronically-controlled sequence selective alkylation of DNA. All natural compounds showed a cytotoxicity against leukaemia L1210 cell lines in the range 10 -220pM but while CC-1065 showed a good antitumour activity in an in vivo model (optimal dose from 10 -100 µg/g), duocarmycins showed weak antitumour activity. Despite its potency, CC-1065 cannot be used in humans due to eventual fatality. For this reason many scientists have focused their attention on this class of compounds, in order to obtain new derivatives with equal in vitro potency but a better profile in in vivo models. This effect is accompanied by dramatic changes in the morphology of hepatic mitochondria. On this basis, the recent developments on SARs for this class of compounds and their possible use as therapeutic agents are reviewed, with particular emphasis on recent patent literature and, finally, a conclusive opinion will be given on this topic.

Design, Synthesis, and Evaluation of Linker-Duocarmycin Payloads: Toward Selection of HER2-Targeting Antibody–Drug Conjugate SYD985

“…Reduction of the nitro group with zinc under acidic conditions gave amine 19. Next, coupling with methoxymethyl (MOM)-protected 4-hydroxybenzoic acid (20), prepared from methyl 4-hydroxybenzoate through reaction with chloromethyl methyl ether followed by ester hydrolysis, 42 gave ethyl ester 21, which was hydrolyzed with sodium hydroxide in aqueous 1,4-dioxane to provide acid 22.…”

“…Although CC-1065 was shown to be very potent in vitro, it demonstrated only moderate in vivo activity and delayed lethality accompanied by irreversible hepatic toxicity in animal models. Many groups have been working on the development of synthetic duocarmycin analogues with the aim to improve the biological profile of this class of compounds. − …”

Chemical and Biological Explorations of the Family of CC-1065 and the Duocarmycin Natural Products

“…1) are natural products isolated from the culture broth of Streptomyces species, which have been shown to exert ultra-potent activity against cultured cancer cells and in experimental animals [1][2][3]. More recently, (+)-yatakemycin (10) has been isolated from Streptomyces sp.…”

Selective Cancer Therapy by Extracellular Activation of a Highly Potent Glycosidic Duocarmycin Analogue

“…Duocarmycins and CC-1065 are a class of potent natural antitumor products isolated from Streptomyces species that are active at the picomolar level. ,,, CC-1065 and related synthetic analogues such as adozelesin, carzelesin, and bizelesin, however, have limited therapeutic efficacy due to excessive systemic toxicity in preclinical studies. − Prodrugs of anticancer agents can be designed to display conditional activity against cancer cells and reduced toxicity to normal tissues, thereby increasing the therapeutic index. Thus, a series of anticancer prodrugs was developed by conjugating carbohydrate moieties to duocarmycin analogues. − , In addition to reducing systemic toxicity, the glycosidic prodrugs displayed enhanced water solubility and increased in vivo stability by preventing the spontaneously conversion of seco-drug into the cyclopropyl form, which can alkylate DNA in normal cells before the drug reaches the tumor microenvironment.…”