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1.
Bioorg Chem ; 92: 103280, 2019 11.
Article in English | MEDLINE | ID: mdl-31539740

ABSTRACT

Mitomycin C (MC), an anti-cancer drug, and its analog, decarbamoylmitomycin C (DMC), are DNA-alkylating agents. MC is currently used in the clinics and its cytotoxicity is mainly due to its ability to form Interstrand Crosslinks (ICLs) which impede DNA replication and, thereby, block cancer cells proliferation. However, both MC and DMC are also able to generate monoadducts with DNA. In particular, we recently discovered that DMC, like MC, can form deoxyadenosine (dA) monoadducts with DNA. The biological role played by these monoadducts is worthy of investigation. To probe the role of these adducts and to detect them in enzymatic digests of DNA extracted from culture cells treated by both drugs, we need access to reference compounds i.e. MC and DMC dA-mononucleoside adducts. Previous biomimetic methods used to generate MC and DMC mononucleoside adducts are cumbersome and very low yielding. Here, we describe the diastereospecific chemical synthesis of both C-1 epimers of MC and DMC deoxyadenosine adducts. The key step of the synthesis involves an aromatic substitution reaction between a 6-fluoropurine 2'-deoxyribonucleoside and appropriately protected stereoisomeric triaminomitosenes to form protected-MC-dA adducts with either an S or R stereochemical configuration at the adenine-mitosene linkage. Fluoride-based deprotection methods generated the final four reference compounds: the two stereoisomeric MC-dA adducts and the two stereoisomeric DMC-dA adducts. The MC and DMC-dA adducts synthesized here will serve as standards for the detection and identification of such adducts formed in the DNA of culture cells treated with both drugs.


Subject(s)
Deoxyadenosines/chemical synthesis , Mitomycin/chemical synthesis , Mitomycins/chemical synthesis , Alkylation , DNA Adducts/analysis , DNA Adducts/metabolism , Deoxyadenosines/chemistry , Fungal Proteins/metabolism , Mitomycin/chemistry , Mitomycins/chemistry , Molecular Conformation , Single-Strand Specific DNA and RNA Endonucleases/metabolism , Stereoisomerism
2.
Bioorg Chem ; 65: 90-9, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26894558

ABSTRACT

Mitomycin C (MC) and Decarbamoylmitomycin C (DMC) - a derivative of MC lacking the carbamate on C10 - are DNA alkylating agents. Their cytotoxicity is attributed to their ability to generate DNA monoadducts as well as intrastrand and interstrand cross-links (ICLs). The major monoadducts generated by MC and DMC in tumor cells have opposite stereochemistry at carbon one of the guanine-mitosene bond: trans (or alpha) for MC and cis (or beta) for DMC. We hypothesize that local disruptions of DNA structure from trans or cis adducts are responsible for the different biochemical responses produced by MC and DMC. Access to DNA substrates bearing cis and trans MC/DMC lesions is essential to verify this hypothesis. Synthetic oligonucleotides bearing trans lesions can be obtained by bio-mimetic methods. However, this approach does not yield cis adducts. This report presents the first chemical synthesis of a cis mitosene DNA adduct. We also examined the stereopreference exhibited by the two drugs at the mononucleotide level by analyzing the formation of cis and trans adducts in the reaction of deoxyguanosine with MC or DMC using a variety of activation conditions. In addition, we performed Density Functional Theory calculations to evaluate the energies of these reactions. Direct alkylation under autocatalytic or bifunctional conditions yielded preferentially alpha adducts with both MC and DMC. DFT calculations showed that under bifunctional activation, the thermodynamically favored adducts are alpha, trans, for MC and beta, cis, for DMC. This suggests that the duplex DNA structure may stabilize/oriente the activated pro-drugs so that, with DMC, formation of the thermodynamically favored beta products are possible in a cellular environment.


Subject(s)
DNA Adducts/chemical synthesis , Deoxyguanosine/chemical synthesis , Mitomycin/chemical synthesis , Mitomycins/chemical synthesis , DNA Adducts/chemistry , Deoxyguanosine/chemistry , Mitomycin/chemistry , Mitomycins/chemistry , Molecular Conformation , Quantum Theory
3.
Angew Chem Int Ed Engl ; 53(35): 9302-5, 2014 Aug 25.
Article in English | MEDLINE | ID: mdl-25044229

ABSTRACT

A DNA crosslinking approach, which is distinct but related to the double alkylation by mitomycin C, involving a novel electrophilic spiro-cyclopropane intermediate is hypothesized. Rational design and substantial structural simplification permitted the expedient chemical synthesis and rapid discovery of MTSB-6, a mitomycin C analogue which is twice as potent as mitomycin C against the prostate cancer cells. MTSB-6 shows improvements in its selective action against noncancer prostate cells over mitomycin C. This hypothesis-driven discovery opens novel yet synthetically accessible mitosene structural space for discovering more potent and less toxic therapeutic candidates.


Subject(s)
Mitomycin/pharmacology , Mitomycins/chemistry , Mitomycins/pharmacology , Cell Line , Cell Survival/drug effects , Dose-Response Relationship, Drug , Humans , Inhibitory Concentration 50 , Mitomycin/chemistry , Mitomycins/chemical synthesis , Molecular Structure , Structure-Activity Relationship
4.
J Org Chem ; 78(12): 6245-52, 2013 Jun 21.
Article in English | MEDLINE | ID: mdl-23721078

ABSTRACT

The preparation of trans-2,3-disubstituted indolines from 1-azido-2-allylbenzene derivatives via a diastereoselective radical cascade using ethyl iodoacetate and triethylborane is described. Further lactamization afforded substituted benzopyrrolizidinones with excellent diastereomeric ratios. The radical cascade/lactamization sequence was efficiently applied to the synthesis of a 3-oxo-leucomitosane related to the mitomycin family of alkaloids.


Subject(s)
Allyl Compounds/chemistry , Benzene Derivatives/chemistry , Indoles/chemical synthesis , Mitomycins/chemical synthesis , Boranes/chemistry , Iodoacetates/chemistry , Molecular Structure , Stereoisomerism
6.
Arch Pharm Res ; 35(8): 1413-20, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22941484

ABSTRACT

We report the design and synthesis of two new mitomycin dimers, 7-N,7'-N'-(1″,2″-dithiepanyl-3″,7″-dimethylenyl)bismitomycin C (8) and 7-N,7'-N'-(2″,6″-dihydroxy-1″,7″-heptanediyl)bismitomycin C (9). Mitomycins 8 and 9 are dimers connected by a seven-membered cyclic disulfide (a 1,2-dithiepane) and a 2,6-dihydroxyheptane linkers, respectively. Mitomycin 8 was designed to undergo efficient nucleophilic activation and following alkylation to give DNA adducts such as DNA interstrand cross-link (DNA ISC) adducts. The key moiety in 8 is a seven-membered cyclic disulfide linker that can generate two thiol groups in a molecule through disulfide cleavage. The two thiols can serve as probes to activate two mitomycin rings by intramolecular cyclization to quinone rings. The mitomycin 8 was synthesized using mitomycin A (1) and the key intermediate, cyclic disulfide 11 that was prepared through a nine-step synthetic sequence from 1,6-heptadiene (12). The diol mitomycin 9 was also synthesized from 1 and diamine salt 15.


Subject(s)
Antibiotics, Antineoplastic/chemistry , Mitomycins/chemistry , Antibiotics, Antineoplastic/chemical synthesis , Dimerization , Mitomycins/chemical synthesis
7.
Angew Chem Int Ed Engl ; 51(34): 8624-7, 2012 Aug 20.
Article in English | MEDLINE | ID: mdl-22847823

ABSTRACT

What a ring formation! Bicyclic dihydropyrrolizines with an electron-withdrawing group (EWG) at the 5-position are formed in one step from linear azidoenynes under gold catalysis. This novel route involves the use of azide as a nitrene precursor, electronically-controlled regioselectivity, and the generation of destabilized 1-azapentadienium ions and their pericyclic reactions. This method was used for a formal synthesis of 7-methoxymitosene.


Subject(s)
Anti-Bacterial Agents/chemical synthesis , Gold/chemistry , Mitomycins/chemical synthesis , Pyrroles/chemical synthesis , Anti-Bacterial Agents/chemistry , Catalysis , Chemistry, Pharmaceutical , Mitomycins/chemistry , Molecular Structure , Pyrroles/chemistry , Stereoisomerism
8.
Bioorg Med Chem ; 19(13): 4004-13, 2011 Jul 01.
Article in English | MEDLINE | ID: mdl-21658959

ABSTRACT

Dimeric DNA alkylating agents have drawn significant interest because these compounds are expected to provide at least two reactive sites and as a result, generate enhanced levels of DNA interstrand cross-link (DNA ISC) adducts compared to their monomeric agents. We report the synthesis and mechanistic studies of a novel mitomycin dimer, 7-N,7'-N'-(1″,2″-dithiocanyl-3″,8″-dimethylenyl)bismitomycin C (8) connected by an eight-membered cyclic disulfide. Mitomycins require prior activation (i.e., transformation to a good electrophile) for DNA adduction and therefore, 8 was aimed to undergo facile nucleophilic activation and produce enhanced levels of DNA ISC. At the core of this function lies a cyclic disulfide in 8. It was expected that disulfide cleavage by an appropriate nucleophile would successively produce two thiols that may trigger activation of two mitomycin rings in a dimer through intramolecular cyclization to quinine rings. Compound 8 was synthesized from mitomycin A (1) and the key intermediate, cyclic disulfide (11), along with the reference diol mitomycin 7-N,7'-N'-(2″,7″-dihydroxy-1″,8″-octanediyl)bismitomycin C (23) which does not contain the disulfide unit. We found that 8 underwent significantly enhanced nucleophilic activation in the presence of Et(3)P compared with 23, and that the disulfide unit in 8 played a key role for the nucleophilic activation. Based on these findings, we proposed a mechanism for nucleophilic activation of 8. We further demonstrated that 8 generated much higher levels of DNA ISC (94%) compared with 23 (4%) and 2 (3%) in the presence of Et(3)P (and L-DTT) leading to the conclusion that 8 is more efficient for DNA ISC processes than 23 and 2 due to the role of disulfide unit.


Subject(s)
Alkylating Agents/chemical synthesis , Disulfides/chemistry , Mitomycin/chemistry , Mitomycins/chemical synthesis , Alkylating Agents/chemistry , DNA/chemistry , Dimerization , Disulfides/chemical synthesis , Mitomycin/chemical synthesis , Mitomycins/chemistry
9.
Chemistry ; 17(28): 7890-903, 2011 Jul 04.
Article in English | MEDLINE | ID: mdl-21618622

ABSTRACT

FR900482 and the mitomycins are two intriguing classes of alkaloid natural products that have analogous biological mechanisms and obvious structural similarity. Both classes possess potent anticancer activity, a feature that has led to their investigation and implementation for the clinical treatment of human cancer. Given the structural similarity between these natural products, we envisioned a common synthetic strategy by which both classes could be targeted through assembling the mitomycin skeleton prior to further oxidative functionalization. Realization of this strategy with respect to FR900482 was accomplished through the synthesis of 7-epi-FR900482, which displayed equal potency relative to the natural product against two human cancer cell lines. With the challenging goal of a synthesis of either mitomycin or FR900482 in mind, several methodologies were explored. While not all of these methods ultimately proved useful for our synthetic goal, a number of them led to intriguing findings that provide a more complete understanding of several methodologies. In particular, amination via π-allyl palladium complexes for the synthesis of tetrahydroquinolines, eight-membered heterocycle formation via carbonylative lactamization, and amination through late-stage C-H insertion via rhodium catalysis all featured prominently in our synthetic studies.


Subject(s)
Mitomycins/chemistry , Mitomycins/chemical synthesis , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Biological Products/chemistry , Drug Design , Humans , Molecular Structure , Oxazines/chemical synthesis , Oxazines/chemistry , Stereoisomerism
10.
Anticancer Agents Med Chem ; 9(4): 369-80, 2009 May.
Article in English | MEDLINE | ID: mdl-19442038

ABSTRACT

The 8H-thieno[2,3-b]pyrrolizinones, some of which exert very potent cytotoxic activity against tumor cell lines in vitro, are a promising novel series of anti-cancer agents. These compounds belong to the tripentone family and are based on 9H-pyrrolo[1,2-a]indol-9-one derivatives and their heterocyclic isosteres. This paper inventories the different synthetic strategies for tripentones and reviews their biological effects and therapeutic potential.


Subject(s)
Antineoplastic Agents/chemical synthesis , Mitomycins/pharmacology , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Drug Screening Assays, Antitumor , Inhibitory Concentration 50 , Leukemia L1210/drug therapy , Mitomycins/chemical synthesis , Structure-Activity Relationship
11.
J Am Chem Soc ; 130(29): 9556-65, 2008 Jul 23.
Article in English | MEDLINE | ID: mdl-18588303

ABSTRACT

The cancer chemotherapeutic agent mitomycin C (MC) alkylates and cross-links DNA monofunctionally and bifunctionally in vivo and in vitro, forming six major MC-deoxyguanosine adducts of known structures. The synthesis of one of the monoadducts (8) by the postoligomerization method was accomplished both on the nucleoside and oligonucleotide levels, the latter resulting in the site-specific placement of 8 in a 12-mer oligodeoxyribonucleotide 26. This is the first application of this method to the synthesis of a DNA adduct of a complex natural product. Preparation of the requisite selectively protected triaminomitosenes 14 and 24 commenced with removal of the 10-carbamoyl group from MC, followed by reductive conversion to 10-decarbamoyl-2,7-diaminomitosene 10. This substance was transformed to 14 or 24 in several steps. Both were successfully coupled to the 2-fluoro-O(6)-(2-trimethylsilylethyl)deoxyinosine residue of the 12-mer oligonucleotide. The N(2)-phenylacetyl protecting group of 14 after its coupling to the 12-mer oligonucleotide could not be removed by penicillinamidase as expected. Nevertheless, the Teoc protecting group of 24 after coupling to the 12-mer oligonucleotide was removed by treatment with ZnBr2 to give the adducted oligonucleotide 26. However, phenylacetyl group removal was successful on the nucleoside-level synthesis of adduct 8. Proof of the structure of the synthetic nucleoside adduct included HPLC coelution and identical spectral properties with a natural sample, and (1)H NMR. Structure proof of the adducted oligonucleotide 26 was provided by enzymatic digestion to nucleosides and authentic adduct 8, as well as MS and MS/MS analysis.


Subject(s)
DNA Adducts/chemical synthesis , Mitomycin/chemical synthesis , Oligodeoxyribonucleotides/chemical synthesis , Chromatography, High Pressure Liquid , Circular Dichroism , DNA Adducts/chemistry , Inosine/analogs & derivatives , Inosine/chemistry , Mitomycin/chemistry , Mitomycins/chemical synthesis , Mitomycins/chemistry , Nucleosides/chemical synthesis , Nucleosides/chemistry , Oligodeoxyribonucleotides/chemistry , Spectrophotometry, Ultraviolet , Tandem Mass Spectrometry , Trimethylsilyl Compounds/chemistry
12.
Chem Soc Rev ; 36(8): 1207-26, 2007 Aug.
Article in English | MEDLINE | ID: mdl-17619682

ABSTRACT

This tutorial review provides a historical sampling of synthetic efforts undertaken in our laboratory, which have led to the total syntheses of a range of small molecule natural products of potential interest in oncology. It has become evident that natural products, and structures clearly derivable from natural products, have a remarkable record in the treatment of cancer at the clinical level. It is likely that, with the growing power of chemical synthesis, small molecule natural products will play a continuing role in providing lead anticancer compounds.


Subject(s)
Antineoplastic Agents/chemical synthesis , Amaryllidaceae Alkaloids/chemical synthesis , Amaryllidaceae Alkaloids/chemistry , Antibiotics, Antineoplastic/chemical synthesis , Antibiotics, Antineoplastic/chemistry , Antineoplastic Agents/chemistry , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Isoquinolines/chemical synthesis , Isoquinolines/chemistry , Macrolides/chemical synthesis , Macrolides/chemistry , Mitomycins/chemical synthesis , Mitomycins/chemistry , Tubulin Modulators/chemical synthesis , Tubulin Modulators/chemistry
13.
Chem Res Toxicol ; 18(2): 213-23, 2005 Feb.
Article in English | MEDLINE | ID: mdl-15720125

ABSTRACT

Mitomycin C (MC) is a cytotoxic and mutagenic antitumor agent that alkylates and cross-links DNA. These effects are dependent on reductive bioactivation of MC. 2,7-Diaminomitosene (2,7-DAM) is the major metabolite of MC in tumor cells, generated by the reduction of MC. 2,7-DAM alkylates DNA in the cell in situ, forming an adduct at the N7 position of 2'-deoxyguanosine (2,7-DAM-dG-N7). To determine the biological effects of this adduct, we have synthesized an oligonucleotide containing a single 2,7-DAM-dG-N7 adduct and inserted it into an M13 bacteriophage genome. Replication of this construct in repair-competent Escherichia coli showed that the adduct was only weakly toxic and generated approximately 50% progeny as compared to control. No mutant was isolated after analysis of more than 4000 progeny phages from SOS-induced or uninduced host cells; therefore, we estimate that the mutation frequency of 2,7-DAM-dG-N7 was less than 2 x 10(-4) in E. coli. Subsequently, to determine if this adduct might be mutagenic in mammalian cells, it was incorporated into a single-stranded shuttle phagemid vector, pMS2, and replicated in simian kidney (COS-7) cells. Analysis of the progeny showed that mutational frequency of a site specific 2,7-DAM-dG-N7 was not higher than the spontaneous mutation frequency in simian kidney cells. In parallel experiments in cell free systems, template oligonucleotides containing a single 2,7-DAM-dG-N7 adduct directed selective incorporation of cytosine in the 5'-32P-labeled primer strands opposite the adducted guanine, catalyzed by Klenow (exo-) DNA polymerase. The adducted templates also supported full extension of primer strands by Klenow (exo-) and T7 (exo-) DNA polymerases and partial extension by DNA polymerase eta. The innocuous behavior of the 2,7-DAM-dG-N7 monoadduct in vivo and in vitro is in sharp contrast to that of the toxic MC-dG-N2 monoadduct reported earlier.


Subject(s)
DNA Adducts/chemistry , DNA Damage , Mitomycin/chemistry , Mitomycins/chemistry , Animals , COS Cells , DNA/drug effects , Escherichia coli/chemistry , Escherichia coli/drug effects , Mitomycins/chemical synthesis , Mitomycins/pharmacology , Molecular Structure , Mutagenicity Tests , Oligonucleotides/chemical synthesis , Oligonucleotides/chemistry , Oligonucleotides/pharmacology
14.
Org Biomol Chem ; 3(3): 471-82, 2005 Feb 07.
Article in English | MEDLINE | ID: mdl-15678185

ABSTRACT

Dimeric alkylating agents that modify complementary DNA strands have engendered significant interest. We have prepared the novel dimeric mitomycin, 7-N,7'-N'-(1",2"-dithianyl-3",6"-dimethylenyl)bismitomycin C (9), in which the mitomycins are bridged by a dithiane unit. Dimer 9, like the clinically tested acyclic disulfides KW-2149 (3) and BMS-181174 (4), was designed to activate under nucleophilic and reductive conditions. Successive nucleophile-mediated disulfide cleavage transformations of 9 are expected to generate thiol species ideally positioned to render the two mitomycin systems vulnerable to nucleophilic attack and permit DNA interstrand cross-link formation. The dithiane linker, strategically positioned between the two mitomycins, distinguished 9 from 3 and 4. Nucleophilic activation of this cyclic disulfide permitted both activated mitomycins to remain tethered to one another. We report the synthesis of 9, and show that the nucleophile Et(3)P markedly enhances the activation and consumption of 9, compared with the reference compound 7-N, 7"-N'-(cyclohexanyl-trans-1",4"-dimethylenyl)bismitomycin C (27). We further demonstrated that provides higher levels of DNA interstrand cross-links than either the dimeric reference compounds, and 7-N,7-N'-(2",5"-dihydroxy-1",6"-hexanediyl)bismitomycin C (28), or the monomeric mitomycins, 1 and 3, when Et(3)P is added to solutions containing EcoRI-linearized pBR322 DNA.


Subject(s)
Cross-Linking Reagents/chemistry , DNA/chemistry , Mitomycins/chemistry , Binding Sites , Cell Line, Tumor , Cell Proliferation/drug effects , Cross-Linking Reagents/chemical synthesis , Cross-Linking Reagents/pharmacology , DNA/drug effects , Dimerization , Drug Screening Assays, Antitumor , Humans , Mitomycins/chemical synthesis , Mitomycins/pharmacology , Molecular Conformation , Stereoisomerism , Structure-Activity Relationship
15.
J Med Chem ; 47(12): 3308-19, 2004 Jun 03.
Article in English | MEDLINE | ID: mdl-15163210

ABSTRACT

The three dimers 3, 4, and 5 of mitomycin C (MC), a natural antibiotic and cancer chemotherapeutic agent, were synthesized in which two MC molecules were linked with -(CH(2))(4)-, -(CH(2))(12)-, and -(CH(2))(3)N(CH(3))(CH(2))(3)- tethers, respectively. The dimeric mitomycins were designed to react as polyfunctional DNA alkylators, generating novel types of DNA damage. To test this design, their in vitro DNA alkylating and interstrand cross-linking (ICL) activities were studied in direct comparison with MC, which is itself an ICL agent. Evidence is presented that 3-5 multifunctionally alkylate and cross-link extracellular DNA and form DNA ICLs more efficiently than MC. Reductive activation, required for these activities, is catalyzed by the same reductases and chemical reductants that activate MC. Dimer 5, but not MC, cross-linked DNA under activation by low pH also. Sequence specificities of cross-linking of a 162-bp DNA fragment (tyrT DNA) by MC, 3, and 5 were determined using DPAGE. The dimers and MC cross-linked DNA with the same apparent CpG sequence specificity, but 5 exhibited much greater cross-linking efficacy than MC. Greatly enhanced regioselectivity of cross-linking to G.C rich regions by 5 relative to MC was observed, for which a mechanism unique to dimeric MCs is proposed. Covalent dG adducts of 5 with DNA were isolated and characterized by their UV and mass spectra. Tri- and tetrafunctional DNA adducts of 5 were detected. Although the dimers were generally less cytotoxic than MC, dimer 5 was highly and uniformly cytotoxic to all 60 human tumor cell cultures of the NCI screen. Its cytotoxicity to EMT6 tumor cells was enhanced under hypoxic conditions. These findings together verify the expected features of the MC dimers and warrant further study of the biological effects of dimer 5.


Subject(s)
Antineoplastic Agents, Alkylating/chemical synthesis , Cross-Linking Reagents/chemical synthesis , DNA/chemistry , Mitomycins/chemical synthesis , Animals , Antineoplastic Agents, Alkylating/chemistry , Antineoplastic Agents, Alkylating/pharmacology , Catalysis , Cross-Linking Reagents/chemistry , Cross-Linking Reagents/pharmacology , Dimerization , Drug Screening Assays, Antitumor , Electrophoresis, Polyacrylamide Gel , Humans , Mass Spectrometry , Mice , Micrococcus luteus , Mitomycin/chemical synthesis , Mitomycin/chemistry , Mitomycin/pharmacology , Mitomycins/chemistry , Mitomycins/pharmacology , Oligonucleotides/chemistry , Oxidation-Reduction , Spectrophotometry, Ultraviolet , Stereoisomerism
16.
J Am Chem Soc ; 125(51): 15796-806, 2003 Dec 24.
Article in English | MEDLINE | ID: mdl-14677970

ABSTRACT

An enantiocontrolled route to aziridinomitosenes had been developed from l-serine methyl ester hydrochloride. The tetracyclic target ring system was assembled by an internal azomethine ylide cycloaddition reaction based on silver ion-assisted intramolecular oxazole alkylation and cyanide-induced ylide generation via a labile oxazoline intermediate (62 to 66). Other key steps include reductive detritylation of 26, methylation of the N-H aziridine 56, oxidation of the sensitive cyclohexenedione 68 to quinone 70, and carbamoylation using Fmoc-NCO. Although the aziridinomitosene tetracycle is sensitive, a range of protecting group manipulations and redox chemistry can be performed if suitable precautions are taken. A study of DNA alkylation by the first C-6,C-7-unsubstituted aziridinomitosene 11a has been carried out, and evidence for DNA cross-link formation involving nucleophilic addition to the quinone subunit is described.


Subject(s)
Aziridines/chemistry , Aziridines/pharmacology , DNA/drug effects , DNA/metabolism , Mitomycins/chemistry , Mitomycins/pharmacology , Alkylation/drug effects , Aziridines/chemical synthesis , Mitomycins/chemical synthesis , Stereoisomerism
17.
J Am Chem Soc ; 124(5): 748-9, 2002 Feb 06.
Article in English | MEDLINE | ID: mdl-11817939

ABSTRACT

Treatment of 11a with methyllithium affords the destannylated product 12 together with a small amount of tetracyclic product derived from intramolecular Michael addition. The same procedure from the deuterated analogue 11b gives the tetracyclic 18 as the major product, the result of a substantial kinetic deuterium isotope effect that favors formation of 16 and 17 by suppressing indole ring lithiation to the undesired 15. When the product mixture is quenched with phenylselenenyl chloride, 17 is converted into the aziridinomitosene 19 in 80% yield. Conversion into the aziridinomitosene alcohol 21 and the deprotected aziridine 20 is also demonstrated.


Subject(s)
Aziridines/chemical synthesis , Deuterium/chemistry , Mitomycins/chemical synthesis , Anions , Mitomycins/chemistry
18.
Org Lett ; 2(23): 3619-21, 2000 Nov 16.
Article in English | MEDLINE | ID: mdl-11073659

ABSTRACT

A facile fragmentation of beta-alkyl-beta-aryl-alpha-oxo-gamma-butyrolactones is reported. A study to assist in the elucidation of the mechanism of the reaction is also revealed.


Subject(s)
Antibiotics, Antineoplastic/chemical synthesis , Butyrates/chemistry , Lactones/chemistry , Mitomycins/chemical synthesis , Antibiotics, Antineoplastic/chemistry , Indicators and Reagents , Mitomycins/chemistry , Stereoisomerism
20.
Biochemistry ; 39(19): 5817-30, 2000 May 16.
Article in English | MEDLINE | ID: mdl-10801332

ABSTRACT

Described herein is a study of the reductive alkylation chemistry of mitosene antitumor agents. We employed a 13C-enriched electrophilic center to probe the fate of the iminium ion resulting from reductive activation. The 13C-labeled center permitted the identification of complex products resulting from alkylation reactions. In the case of DNA reductive alkylation, the type and number of alkylation sites were readily assessed by 13C NMR. Although there has been much excellent work done in the area of mitosene chemistry and biochemistry, the present study provides a number of new findings: (1) The major fate of the iminium ion is head-to-tail polymerization, even in dilute solutions. (2) Dithionite reductive activation results in the formation of mitosene sulfite esters as well as the previously observed sulfonate adducts. (3) The mitosene iminium ion alkylates the adenosine 6-amino group as well as the guanosine 2-amino group. The identification of the latter adduct was greatly facilitated by the 13C-label at the electrophilic center. (4) The mitosene iminium ion alkylates DNA at both nitrogen and oxygen centers without any apparent base selectivity. The complexity of mitosene reductive alkylation of DNA will require continued adduct isolation studies.


Subject(s)
Antineoplastic Agents, Alkylating/chemistry , DNA Adducts/chemistry , Imines/chemistry , Mitomycins/chemistry , Antineoplastic Agents, Alkylating/chemical synthesis , Antineoplastic Agents, Alkylating/isolation & purification , Buffers , Carbon Isotopes , Deoxyadenosines/chemistry , Deoxyguanosine/chemistry , Dithionite/chemistry , Mitomycins/chemical synthesis , Mitomycins/isolation & purification , Nuclear Magnetic Resonance, Biomolecular , Oxidation-Reduction , Reducing Agents/chemistry
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