Did you mean: duocarmycin
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Current Pharmaceutical Design 2002The duocarmycins and (+)-CC-1065 are amongst the most potent antitumour antibiotics discovered to date and yet have not progressed into the clinic. The natural products... (Review)
Review
The duocarmycins and (+)-CC-1065 are amongst the most potent antitumour antibiotics discovered to date and yet have not progressed into the clinic. The natural products are extremely stable to nucleophilic attack until bound to their DNA target and are not substrates for any other biological nucleophile. The mechanism for this target activation of the duocarmycins is discussed with relation to both an acid-catalyzed activation and a binding-induced conformational change leading to ground state destabilization. It is suggested that targeting of the duocarmycins to their site of action in a tumour may be more important than introducing systemically-activated prodrugs as the natural product itself can be considered to be a type of prodrug, activated only on binding to its targets. Methods that have been used to target CC-1065 and the duocarmycins are reviewed as well as efforts towards systemically activated prodrugs. A simple analysis of the approaches that could be taken to vary the structure for targeting is suggested.
Topics: Animals; Antibiotics, Antineoplastic; Antineoplastic Agents, Alkylating; Cell Survival; DNA; Drug Stability; Duocarmycins; Indoles; Leucomycins; Leukemia L1210; Prodrugs; Pyrroles; Pyrrolidinones; Structure-Activity Relationship; Tumor Cells, Cultured
PubMed: 12052214
DOI: 10.2174/1381612023394539 -
Drug Discovery Today Feb 2021The duocarmycins belong to a class of agent that has fascinated scientists for over four decades. Their exquisite potency, unique mechanism of action, and efficacy in... (Review)
Review
The duocarmycins belong to a class of agent that has fascinated scientists for over four decades. Their exquisite potency, unique mechanism of action, and efficacy in multidrug-resistant tumour models makes them attractive to medicinal chemists and drug hunters. However, despite great advances in fine-tuning biological activity through structure-activity relationship studies (SARS), no duocarmycin-based therapeutic has reached clinical approval. In this review, we provide an overview of the most promising strategies currently used and include both tumour-targeted prodrug approaches and antibody-directed technologies.
Topics: Animals; Antibodies; Antineoplastic Agents, Alkylating; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Duocarmycins; Humans; Neoplasms; Prodrugs; Structure-Activity Relationship
PubMed: 33232841
DOI: 10.1016/j.drudis.2020.11.020 -
JACS Au Dec 2022Synthetic analogues of the DNA-alkylating cytotoxins of the duocarmycin class have been extensively investigated in the past 40 years, driven by their high potency,... (Review)
Review
Synthetic analogues of the DNA-alkylating cytotoxins of the duocarmycin class have been extensively investigated in the past 40 years, driven by their high potency, their unusual mechanism of bioactivity, and the beautiful modularity of their structure-activity relationship (SAR). This Perspective analyzes how the molecular designs of synthetic duocarmycins have evolved: from (1) early SAR studies, through to modern applications for directed cancer therapy as (2) prodrugs and (3) antibody-drug conjugates in late-stage clinical development. Analyzing 583 primary research articles and patents from 1978 to 2022, we distill out a searchable A0-format "Minard map" poster of ca. 200 key structure/function-tuning steps tracing chemical developments across these three key areas. This structure-based overview showcases the ingenious approaches to tune and target bioactivity, that continue to drive development of the elegant and powerful duocarmycin platform.
PubMed: 36590260
DOI: 10.1021/jacsau.2c00448 -
Anti-cancer Agents in Medicinal... Mar 2009In recent years, a series of new and highly cytotoxic analogues of CC-1065 and the duocarmycins have been developed that can be transformed into much less toxic prodrugs... (Review)
Review
In recent years, a series of new and highly cytotoxic analogues of CC-1065 and the duocarmycins have been developed that can be transformed into much less toxic prodrugs for the use in antibody-directed enzyme prodrug therapy (ADEPT), gene-directed enzyme prodrug therapy (GDEPT) and prodrug monotherapy (PMT) of cancer. In all these approaches, a relatively non-toxic prodrug is applied and subsequently converted selectively in the tumour tissue into a highly cytotoxic drug, thus reducing undesired side effects accompanying conventional chemotherapy. Here, the design and biological evaluation of prodrugs based on analogues of CC-1065 and the duocarmycins for the use in tumour selective cancer therapies is reviewed. The advantage of this approach is the excellent therapeutic index of some of the new prodrugs of over 5000 and the high cytotoxicity of the corresponding drugs with IC(50) values of as low as 16 pM (IC(50): concentration required for 50 % growth inhibition of target cells). In addition, a novel method for the correlation of the alkylation efficiency and the cytotoxicity based on mass spectrometry is described.
Topics: Animals; Antineoplastic Agents; Cell Proliferation; Drug Design; Drug Screening Assays, Antitumor; Duocarmycins; Humans; Indoles; Neoplasms; Prodrugs; Pyrrolidinones
PubMed: 19275523
DOI: 10.2174/1871520610909030304 -
Proceedings of the National Academy of... Apr 1995Key studies defining the DNA alkylation properties and selectivity of a new class of exceptionally potent, naturally occurring antitumor antibiotics including CC-1065,... (Comparative Study)
Comparative Study Review
Key studies defining the DNA alkylation properties and selectivity of a new class of exceptionally potent, naturally occurring antitumor antibiotics including CC-1065, duocarmycin A, and duocarmycin SA are reviewed. Recent studies conducted with synthetic agents containing deep-seated structural changes and the unnatural enantiomers of the natural products and related analogs have defined the structural basis for the sequence-selective alkylation of duplex DNA and fundamental relationships between chemical structure, functional reactivity, and biological properties. The agents undergo a reversible, stereoelectronically controlled adenine-N3 addition to the least substituted carbon of the activated cyclopropane within selected AT-rich sites. The preferential AT-rich non-covalent binding selectivity of the agents within the narrower, deeper AT-rich minor groove and the steric accessibility to the alkylation site that accompanies deep AT-rich minor groove penetration control the sequence-selective DNA alkylation reaction and stabilize the resulting adduct. For the agents that possess sufficient reactivity to alkylate DNA, a direct relationship between chemical or functional stability and biological potency has been defined.
Topics: Alkylating Agents; Antibiotics, Antineoplastic; Base Sequence; Binding Sites; Consensus Sequence; DNA; Duocarmycins; Indoles; Leucomycins; Models, Molecular; Molecular Sequence Data; Molecular Structure; Nucleic Acid Conformation; Pyrroles; Structure-Activity Relationship
PubMed: 7731958
DOI: 10.1073/pnas.92.9.3642 -
Journal of Medicinal Chemistry Oct 2009
Review
Topics: Alkylating Agents; Antibiotics, Antineoplastic; Duocarmycins; Indoles; Molecular Structure; Pyrroles; Structure-Activity Relationship
PubMed: 19639994
DOI: 10.1021/jm9006214 -
Molecular Cancer Therapeutics Nov 2020B7-H3, also referred to as CD276, is a member of the B7 family of immune regulatory proteins. B7-H3 is overexpressed on many solid cancers, including prostate cancer,...
B7-H3, also referred to as CD276, is a member of the B7 family of immune regulatory proteins. B7-H3 is overexpressed on many solid cancers, including prostate cancer, renal cell carcinoma, melanoma, squamous cell carcinoma of the head and neck, non-small cell lung cancer, and breast cancer. Overexpression of B7-H3 is associated with disease severity, risk of recurrence and reduced survival. In this article, we report the preclinical development of MGC018, an antibody-drug conjugate targeted against B7-H3. MGC018 is comprised of the cleavable linker-duocarmycin payload, valine-citrulline- duocarmycin hydroxybenzamide azaindole (vc--DUBA), conjugated to an anti-B7-H3 humanized IgG1/kappa mAb through reduced interchain disulfides, with an average drug-to-antibody ratio of approximately 2.7. MGC018 exhibited cytotoxicity toward B7-H3-positive human tumor cell lines, and exhibited bystander killing of target-negative tumor cells when cocultured with B7-H3-positive tumor cells. MGC018 displayed potent antitumor activity in preclinical tumor models of breast, ovarian, and lung cancer, as well as melanoma. In addition, antitumor activity was observed toward patient-derived xenograft models of breast, prostate, and head and neck cancer displaying heterogeneous expression of B7-H3. Importantly, MGC018 exhibited a favorable pharmacokinetic and safety profile in cynomolgus monkeys following repeat-dose administration. The antitumor activity observed preclinically with MGC018, together with the positive safety profile, provides evidence of a potentially favorable therapeutic index and supports the continued development of MGC018 for the treatment of solid cancers. GRAPHICAL ABSTRACT: http://mct.aacrjournals.org/content/molcanther/19/11/2235/F1.large.jpg.
Topics: Animals; B7 Antigens; Bystander Effect; Cell Line, Tumor; Cell Survival; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Monitoring; Gene Knockdown Techniques; Humans; Immune Checkpoint Inhibitors; Immunoconjugates; Mice; Neoplasms; Treatment Outcome; Xenograft Model Antitumor Assays
PubMed: 32967924
DOI: 10.1158/1535-7163.MCT-20-0116 -
Chemical & Pharmaceutical Bulletin Mar 1995Seven novel potent antitumor antibiotics, duocarmycins A (1), C1 (2), C2 (3), D (4), B1 (5), B2 (6) and SA (7), were isolated from three independently collected...
Seven novel potent antitumor antibiotics, duocarmycins A (1), C1 (2), C2 (3), D (4), B1 (5), B2 (6) and SA (7), were isolated from three independently collected Streptomyces sp. The complete structures, including absolute stereochemistry, were determined by spectral and chemical studies of those duocarmycins and several derivatives. Duocarmycins A (1) and SA (7) possess a 1,2,7,7a-tetrahydrocycloprop[1,2-c]indol-4-one subunit, a common pharmacophore with that of CC-1065 (10) found from Streptomyces zelensis.
Topics: Alkylating Agents; Antibiotics, Antineoplastic; Chemical Phenomena; Chemistry, Physical; Duocarmycins; Indoles; Magnetic Resonance Spectroscopy; Molecular Structure; Pyrrolidinones; Stereoisomerism; Streptomyces
PubMed: 7774022
DOI: 10.1248/cpb.43.378 -
The Journal of Antibiotics Oct 1991Six duocarmycins have been discovered during our search for new antitumor antibiotics and they showed extremely potent cytotoxic activity with IC50 values of 10(-12)...
Six duocarmycins have been discovered during our search for new antitumor antibiotics and they showed extremely potent cytotoxic activity with IC50 values of 10(-12) M-10(-9) M on HeLa S3 cell. Three different producing strains isolated from soils were taxonomically assigned as Streptomyces. Duocarmycin A was unstable in culture broth, so improved culture conditions were designed to produce a high titer of duocarmycins B1, B2, C1 and C2 which are halogenated seco-compounds of duocarmycin A. Duocarmycin SA, one of the most potent cytotoxic agents yet discovered, was shown to be more stable in culture media than duocarmycin A, despite the structural similarity on their spirocyclopropylhexadienone moiety. In contrast to the duocarmycin A fermentation, no halogenated seco-compounds of duocarmycin SA were detected in culture broth supplemented with Br- or Cl-. All duocarmycins could be produced using one producing strain with improved media and culture conditions.
Topics: Antibiotics, Antineoplastic; Bromine; Carbon; Chlorine; Chromatography, High Pressure Liquid; Duocarmycins; Fermentation; Humans; Hydrogen-Ion Concentration; Indoles; Kinetics; Metals; Microscopy, Electron, Scanning; Nitrogen; Pyrroles; Pyrrolidinones; Streptomyces
PubMed: 1955385
DOI: 10.7164/antibiotics.44.1045 -
JACS Au May 2023[This corrects the article DOI: 10.1021/jacsau.2c00448.].
[This corrects the article DOI: 10.1021/jacsau.2c00448.].
PubMed: 37234106
DOI: 10.1021/jacsau.3c00137