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2.
Org Biomol Chem ; 8(8): 1833-42, 2010 Apr 21.
Article in English | MEDLINE | ID: mdl-20449487

ABSTRACT

The synthesis of the first spacer containing, duocarmycin analogue prodrug was realised, its biological properties evaluated and compared to its counterpart prodrug without a spacer unit. The synthesis comprises the manufacture of the new acetylated derivatives and of two double spacer systems, their activation and coupling to the pharmacophoric seco-drug (+)-. Unprecedented biological results were found as the new prodrug showed a fairly low QIC(50) value of 20, but on the other hand a high stability and very low DNA alkylation efficiency. These findings indicate a changed cytostatic mode of action induced by the self-immolative spacer moiety which was employed.


Subject(s)
Alkylating Agents/chemistry , Anti-Bacterial Agents/chemistry , Cytostatic Agents/chemistry , Indoles/chemistry , Prodrugs/chemistry , Alkylating Agents/chemical synthesis , Alkylating Agents/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Cell Line, Tumor , Cytostatic Agents/chemical synthesis , Cytostatic Agents/pharmacology , DNA/metabolism , Duocarmycins , Humans , Indoles/chemical synthesis , Indoles/pharmacology , Prodrugs/chemical synthesis , Prodrugs/pharmacology , Pyrroles/chemical synthesis , Pyrroles/chemistry , Pyrroles/pharmacology
3.
J Am Chem Soc ; 131(36): 13031-6, 2009 Sep 16.
Article in English | MEDLINE | ID: mdl-19697908

ABSTRACT

Circular dichroism (CD) spectroscopy is a well-known method for the analysis of chiral chemical compounds and is often used for studying the structure and interaction of proteins, DNA and bioactive compounds in solution. Here we demonstrate that CD spectroscopy is also a powerful tool for investigating the cellular uptake and mode of action of drugs in live cells. By means of CD spectroscopy, we identified DNA as the cellular target of several novel anticancer agents based on the highly cytotoxic natural antibiotic CC-1065. Furthermore, time-dependent changes in the CD spectra of drug-treated cells enabled us to rationalize differences in drug cytotoxicity. The anticancer agents rapidly penetrate the cell membrane and bind to cellular DNA as their intracellular target. Thereby, the formation of a reversible noncovalent complex with the DNA is followed by a covalent binding of the drugs to the DNA and the more toxic compounds show a higher stability and a lower alkylation rate. Since no drug manipulation is necessary for this kind of investigation and achiral compounds bound to chiral biomolecules may also show induced CD signals, CD spectroscopy of live cells is not limited to the study of analogues of CC-1065. Thus, it constitutes a general approach for studying the mode of action of bioactive compounds on the cellular and molecular level.


Subject(s)
Antibiotics, Antineoplastic/pharmacology , Circular Dichroism , DNA/metabolism , Indoles/pharmacology , Antibiotics, Antineoplastic/analysis , Antibiotics, Antineoplastic/pharmacokinetics , Cell Line, Tumor , Duocarmycins , Humans , Indoles/analysis , Indoles/pharmacokinetics , Molecular Structure
4.
Chem Biol Drug Des ; 74(3): 205-11, 2009 Sep.
Article in English | MEDLINE | ID: mdl-19660031

ABSTRACT

The antibody-directed enzyme prodrug therapy allows a selective liberation of cytotoxic agents from non-toxic prodrugs in cancerous tissue by targeted antibody-enzyme conjugates. We have developed a series of novel glycosidic prodrugs based on the natural antibiotic CC-1065 and the duocarmycins, which are up to 4800 times less toxic than the drugs liberated from these prodrugs in the presence of the activating enzyme (e.g., beta-D-galactosidase). Furthermore, the drugs show very high cytotoxicities with IC(50) values of as low as 4.5 pm. In this report, we summarize our recent results on the development and biological evaluation of these novel third-generation prodrugs with higher water solubility, higher difference in cytotoxicity between the prodrugs and the corresponding drugs and improved cytotoxicity of the drugs as compared with previous compounds.


Subject(s)
Antibodies, Monoclonal/metabolism , Antineoplastic Agents/chemistry , Neoplasms/drug therapy , Prodrugs/chemistry , beta-Galactosidase/metabolism , Antibodies, Monoclonal/immunology , Antineoplastic Agents/toxicity , Cell Line, Tumor , Drug Design , Duocarmycins , Glycosides/chemistry , Humans , Indoles/toxicity , Prodrugs/toxicity , Pyrroles/toxicity , Stereoisomerism , beta-Galactosidase/chemistry
5.
Anal Bioanal Chem ; 395(2): 437-48, 2009 Sep.
Article in English | MEDLINE | ID: mdl-19641906

ABSTRACT

One of the main problems of anti-cancer therapy is an insufficient differentiation between normal and malignant cells by the known anti-proliferant agents. The antibody-directed enzyme prodrug therapy is a promising approach for a selective treatment of cancer, in which a non-toxic prodrug is enzymatically converted into a highly cytotoxic drug at the surface of malignant cells by a targeted antibody-enzyme conjugate. The transformations and the stability of a very promising novel prodrug and its corresponding cytotoxic derivative were now investigated in detail by high-performance liquid chromatography (HPLC)-mass spectrometry (MS). In order to determine the time-dependent DNA alkylation efficiency and the sequence selectivity of the novel compounds, DNA binding studies using direct electrospray-Fourier transform ion cyclotron resonance-MS (ESI-FTICR-MS) have been performed. These measurements were accompanied by HPLC analyses followed by MS of the separated species to confirm the results of the direct ESI-FTICR-MS measurements. The sites of DNA alkylation could be identified unambiguously by the mass spectrometric fragmentation pattern of the alkylated oligodeoxynucleotides as well as by the results of HPLC followed by MS. A combination of all techniques applied led to a better understanding of the mode of action of the new therapeutics and might be used for an estimation of the cytotoxicity of different prodrugs and drugs since the alkylation efficiency correlates with the bioactivity of the compounds in cell culture investigations.


Subject(s)
Antineoplastic Agents, Alkylating/analysis , Chromatography, High Pressure Liquid/methods , Galactosides/analysis , Prodrugs/analysis , Spectrometry, Mass, Electrospray Ionization/methods , Alkylation , Antineoplastic Agents, Alkylating/metabolism , DNA/chemistry , DNA/metabolism , Drug Stability , Escherichia coli/enzymology , Galactosides/metabolism , Models, Molecular , Prodrugs/metabolism , beta-Galactosidase/metabolism
6.
Anticancer Agents Med Chem ; 9(3): 304-25, 2009 Mar.
Article in English | MEDLINE | ID: mdl-19275523

ABSTRACT

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.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Indoles/chemistry , Indoles/pharmacology , Neoplasms/drug therapy , Prodrugs/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Cell Proliferation/drug effects , Drug Design , Drug Screening Assays, Antitumor , Duocarmycins , Humans , Indoles/chemical synthesis , Neoplasms/pathology , Prodrugs/chemical synthesis , Prodrugs/chemistry , Pyrrolidinones/chemical synthesis , Pyrrolidinones/chemistry , Pyrrolidinones/pharmacology
7.
J Med Chem ; 52(2): 537-43, 2009 Jan 22.
Article in English | MEDLINE | ID: mdl-19143570

ABSTRACT

The synthesis and biological evaluation of novel prodrugs for use in the antibody directed enzyme prodrug therapy (ADEPT) of cancer based on the cytotoxic antibiotic duocarmycin SA (1) are described. In this approach, we investigated the influence of the sugar moiety of the glycosidic prodrug on the QIC(50) values as well as on the stability and the water solubility. The best result was found for prodrug 22 containing an alpha-mannoside moiety with a QIC(50) value of 4500.


Subject(s)
Antibodies/therapeutic use , Glycosides/chemistry , Indoles/chemical synthesis , Indoles/pharmacology , Neoplasms/therapy , Prodrugs/chemical synthesis , Prodrugs/pharmacology , beta-Galactosidase/therapeutic use , Chromatography, High Pressure Liquid , Duocarmycins , Indoles/chemistry , Magnetic Resonance Spectroscopy , Neoplasms/drug therapy , Prodrugs/chemistry , Pyrroles/chemical synthesis , Pyrroles/chemistry , Pyrroles/pharmacology , Spectrometry, Mass, Electrospray Ionization
8.
Toxins (Basel) ; 1(2): 134-50, 2009 12.
Article in English | MEDLINE | ID: mdl-22069536

ABSTRACT

The natural antibiotics CC­1065 and the duocarmycins are highly cytotoxic compounds which however are not suitable for cancer therapy due to their general toxicity. We have developed glycosidic prodrugs of seco-analogues of these antibiotics for a selective cancer therapy using conjugates of glycohydrolases and tumour-selective monoclonal antibodies for the liberation of the drugs from the prodrugs predominantly at the tumour site. For the determination of structure activity relationships of the different seco-drugs, experiments addressing their interaction with synthetic DNA were performed. Using electro-spray mass spectrometry and high performance liquid chromatography, the experiments revealed a correlation of the stability of these drugs with their cytotoxicity in cell culture investigations. Furthermore, it was shown that the drugs bind to AT-rich regions of double-stranded DNA and the more cytotoxic drugs induce DNA fragmentation at room temperature in several of the selected DNA double-strands. Finally, an explanation for the very high cytotoxicity of CC-1065, the duocarmycins and analogous drugs is given.


Subject(s)
Drug Design , Structure-Activity Relationship , Antibiotics, Antineoplastic , Antineoplastic Agents/pharmacology , DNA , Prodrugs
9.
ChemMedChem ; 3(12): 1946-55, 2008 Dec.
Article in English | MEDLINE | ID: mdl-19021160

ABSTRACT

A severe limitation in cancer therapy is the often insufficient differentiation between malign and benign tissue using known chemotherapeutics. One approach to decrease side effects is antibody-directed enzyme prodrug therapy (ADEPT). We have developed new glycosidic prodrugs such as (-)-(1S)-26 b based on the antibiotic (+)-duocarmycin SA ((+)-1) with a QIC(50) value of 3500 (QIC(50)=IC(50) of prodrug/IC(50) of prodrug+enzyme) and an IC(50) value for the corresponding drug (prodrug+enzyme) of 16 pM. The asymmetric synthesis of the precursor (-)-(1S)-19 was performed by arylation of the enantiomerically pure epoxide (+)-(S)-29 (> or = 98 % ee).


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Glycosides/chemical synthesis , Glycosides/pharmacology , Prodrugs/chemical synthesis , Prodrugs/pharmacology , Antineoplastic Agents/chemistry , Cell Line, Tumor , Duocarmycins , Glycosides/chemistry , Humans , Indoles/chemical synthesis , Indoles/chemistry , Indoles/pharmacology , Inhibitory Concentration 50 , Neoplasms/drug therapy , Prodrugs/chemistry , Pyrroles/chemical synthesis , Pyrroles/chemistry , Pyrroles/pharmacology , Stereoisomerism , beta-Galactosidase/metabolism
10.
Chemistry ; 14(9): 2811-8, 2008.
Article in English | MEDLINE | ID: mdl-18214880

ABSTRACT

The synthesis of the novel pentagastrin seco-CBI conjugate 3, which is based on the highly cytotoxic antitumor antibiotic (+)-duocarmycin SA (1), is reported. A key step in the synthesis is the palladium-catalyzed carbonylation of aryl bromide 7 to give the benzyl ester 16, which is transformed into the new seco-CBI derivative 21 bearing a carboxylic acid ester moiety. Subsequent transformation of 21 into an activated ester followed by the introduction of beta-alanine and tetragastrin led to the new pentagastrin drug 3 that contains a peptide moiety for targeting cancer cells expressing CCK-B/gastrin receptors.


Subject(s)
Antineoplastic Agents/chemical synthesis , Indoles/chemistry , Indoles/chemical synthesis , Pentagastrin/analogs & derivatives , Pentagastrin/chemistry , Antineoplastic Agents/chemistry , Catalysis , Cell Proliferation/drug effects , Drug Delivery Systems , Duocarmycins , Esters/chemistry , Molecular Structure , Palladium/chemistry , Pentagastrin/chemical synthesis , Pyrroles/chemistry , Receptor, Cholecystokinin B/biosynthesis , Receptor, Cholecystokinin B/drug effects
11.
Int J Mol Sci ; 9(5): 821-837, 2008 May.
Article in English | MEDLINE | ID: mdl-19325786

ABSTRACT

A novel carbamate prodrug 2 containing a pentagastrin moiety was synthesized. 2 was designed as a detoxified analogue of the highly cytotoxic natural antibiotic duocarmycin SA (1) for the use in a targeted prodrug monotherapy of cancers expressing cholecystokinin (CCK-B)/gastrin receptors. The synthesis of prodrug 2 was performed using a palladium-catalyzed carbonylation of bromide 6, followed by a radical cyclisation to give the pharmacophoric unit 10, coupling of 10 to the DNA-binding subunit 15 and transformation of the resulting seco-drug 3b into the carbamate 2 via addition of a pentagastrin moiety.

12.
Chemistry ; 13(16): 4396-409, 2007.
Article in English | MEDLINE | ID: mdl-17455190

ABSTRACT

Novel diastereomerically pure beta-D-galactosidic prodrugs (+)-12 a-e of the cytotoxic antibiotics CC-1065 and the duocarmycins were prepared for an antibody directed enzyme prodrug therapy (ADEPT) using 4 as a substrate via a radical cyclization to give rac-5 and rac-6 followed by a chromatographic resolution of the enantiomers of rac-5, glycosidation and linkage to the DNA-binding units 10 a-e. These only slightly toxic compounds can be toxified enzymatically by an antibody-beta-D-galactosidase conjugate at the surface of malignant cells to give the cytotoxic drugs, which then alkylate DNA. The new prodrugs were tested in in vitro cytotoxicity assays showing excellent QIC(50) values of 4800 and 4300 for (+)-12 a and (+)-12 b, respectively. The absolute configuration of precursor (+)-5 was determined by comparison of the experimental CD spectrum with the theoretically predicted CD spectra and by X-ray structure analysis.


Subject(s)
Antibiotics, Antineoplastic/pharmacology , Indoles/pharmacology , Lung Neoplasms/drug therapy , Prodrugs/pharmacology , Antibiotics, Antineoplastic/chemical synthesis , Antibiotics, Antineoplastic/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Design , Drug Screening Assays, Antitumor , Duocarmycins , Humans , Indoles/chemical synthesis , Indoles/chemistry , Inhibitory Concentration 50 , Molecular Structure , Prodrugs/chemical synthesis , Prodrugs/chemistry , Pyrroles/chemical synthesis , Pyrroles/chemistry , Pyrroles/pharmacology , Stereoisomerism
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