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Bleomycin A(sub 2) can act as the medium for the oxidative cleavage of double-stranded DNA or RNA by a metal ion and oxygen dependant chemical process. The metal binding domain of the bleomycin A(sub 2) in the full natural product structure controls the selective determination of DNA cleavage although the presence of noncovalently linked tri-and tetrapeptide S cannot show the sequence selective DNA cleavage. The metal binding domain of bleomycin A(sub 2) consists of iron (II) and iron (III) complexes.

The key synthetic analogs of bleomycin A(sub 2) 2-O-(3-O-carbamoyl)-alfa-D-mannopyranoside has the same DNA cleavage efficiency, selectivity, and double strand versus single strand DNA cleavage ratio showing that the DNA cleavage capabilities of the natural agent are uninfluenced by carbonyl groups. The DNA cleavage efficiency, the rate of single strand versus double strand DNA cleavage ratio of demannosyslbleomycin A(sub 2) and deglycobleomycin A(sub 2) shows the DNA cleavage capability of the natural agent is highly affected by the first carbohydrate of the disaccharide.

A new synthetic sequence, based on a Tempo trap of an aryl radical-alkene 5-exo-trig cyclization of an unfunctionalized and unactivated alkene by direct introduction of a 3-(hydroxymethyl)indoline, helps synthesize 1,2,9,9a-tetrahydrocyclopropa(c)benz(e)indol-4-one (CBI). A 9-step synthetic sequence helps convert 1,3-dihydroxynaphthalene into the penultimate CBI precursor with an yield of 33 to 38%.

A new synthesis method is proposed for CC-1065 and duocarmycin analogs that incorporate the 2,3,10, 10a-tetrahydro-1H-cyclopropa(d)benzo(f)quinol-5-one (CBQ) alkylation subunit. The synthesis involves a key 6-exo-trig aryl radical alkene cyclization and subsequent Winstein Ar-3' alkylation. These CBQ-based analogs show marked solvolysis reactivity and mixed solvolysis regioselectivity. These analogs are highly stable and their potent activity is correlated with their chemical stability.

Ullmann macrocyclization methodology helps convert N-methyl-erythro-beta-hydroxy-L-4-iodophenylalanine into functionalized 13-hydroxy-N-methylcycloisodityrosine derivatives, which help synthesize O-methylbouvardin. Selective demethylation of O-methylbouvardin yields bouvardin. NMR study of its conformational properties reveals that additional minor conformations of bouvardin and O-methylbouvardin starts from a cis N(9)-C(8) N-methylamide conformation.

Synthetic schemes that include chromatographic methods help synthesize the potent cytotoxic agent ent- and (+)-CBI-TMI, a vital analog of duocarmycin SA and duocarmycin A. (+)-CBI-TMI is an efficient and selective alkylating agent. A comparison of natural enantiomers of duocarmycin SA, duocarmycin A, CBI-TMI and CI-TMI reveals that solvolysis stability has a linear relationship with cytotoxic potency. Solvolytically stable agents reach their biological targets faster than solvolytically unstable agents.

Thermal Diels-Alder reaction between amidine and 1,3,5-triazines involves tautomerization, (4+2) cycloaddition and a retro-Diels-Alder step, producing substituted 4-aminopyrimidines. Amidine hydrochloride salts yield higher conversions to pyrimidines than free bases in polar, aprotic solvents at moderate temperature. The ratio of dienophile-diene does not influence the reaction, which reaction exhibits triazine substituent effects characteristic of an inverse electron demand Diels-Alder reaction.

Synthesis of an alcohol and its reactive chloride helps prepare a p-quinonemethide analog of the CC-1065 and duocarmycin alkylation subunits. The stability of the p-quinonemethide analog helps its isolation and characterization. Vinylogous amide stabilization and the naphtho-versus benzo-p-quinonemethide structure control the stability p-quinonemethide analog's stability. The analog exhibits a high reactivity with a half-life of less than one minute in a medium of methanol at 25 degree Celsius.

An extension of the total synthesis scheme of deglycobleomycin A(sub 2) and deglycobleomycin A(sub 1) yields various derivatives of glycobleomycin A(sub 2). The C2 acetamido sidechain influences the synthesis. DNA cleavage properties of Fe(II) or Fe(III) complexes of deglycobleomycin derivatives are analyzed and compared. Desimidazolyldeglycobleomycin A(sub 2) exhibits an altered and nonselective cleavage pattern.

The total synthesis of bleomycin A (sub 2) involves the incorporation of the disaccharide subunit 2-O-(3-O-carbamoyl-alpha-D-mannopyranosyl)- L-gulopyranose into the procedure. A diasteroselective alpha-O-glycosidation is the vital step for the synthesis of the disaccharide. Order of assemblage of subunits is critical for the total synthesis of bleomycin A(sub 2).

Inverse electron demand Diels-Alder reaction of 2,4, 6-tris(ethoxycarbonyl)- 1,3,5-triazine is the key step in the synthesis of pyrimidoblamic acid subunits. Optically-active N-acyloxazolidinones undergo an imine addition reaction to introduce the C2 acetamido sidechain to complete the synthesis of (-)pyrimidoblamic acid. The absolute configuration of the C2 acetamido chain is described and is extended for the diastereoselective synthesis of (-)descarboxamidopyrimidoblamic acid.

A concise, diastereocontrolled process yields bleomycin A(sub 2) subunits and optically-active tripeptide S, tetrapeptide S, and pentapeptide S. Absolute DNA binding constants reveal the influence of linking chain substituents on DNA binding strength and the binding site size of the agent. Calculated binding site sizes reveal that the tripeptide S subunit of bleomycin A(sub 2) is fully-bound to duplex DNA.

Thermal cycloaddition reactions between cyclopropenone ketal and oxygenated diene are the basis of the tropolone annulation, applicable to rubrolone C ring introduction. The Diels-Alder reaction produces a (4 + 2) cyclo adduct. The vital step in the synthesis is the conversion of this adduct into norcaradiene. Electrocyclic rearrangement of this norcaradiene and further tautomerization lead to tropolone analogous to that found in rubrolone.

Electrophoresis studies reveal that (+)-duocarmycin SA is more selective and efficient than (+)-duocarmycin A with respect to DNA alkylation due to its greater stability. The N-BOC-DSA enantiomers of duocarmycin SA's alkylation subunit alkylate DNA are similar to each other but less efficient than (+)- or (-)-duocarmycin SA. The studies allow the design of a duocarmycin DNA alkylation model that allows the behavior of both enantiomers.

An analysis of the first total synthesis of (+)-P-3A (1), epi-(-)-P-3A (2) and (-)-desacetamido P-3A (3) confirmed that Fe(II) complexes of 1, 2 and 3 cleave duplex DNA above background Fe(II) almost as well as deglycobleomycin A2, without any noticeable sequence selectivity. A bleomycin-linked metal chelation subunit is inadequate to provide evidence of the typical DNA cleavage selectivity.

Innovative application of the sym-tetrazine 1,2-diazine, pyrrole Diels-Alder strategy is the preparation of isochrysohermidin. A transient blue radical anion cyanohermidin is obtained from the autoxidation of colorless chromogen hermidin, isolated from Mercurialis perennis. Sodium methoxide-promoted rearrangement is related to the dimer of Mercurialis leiocarpa.

The naturally present macrocyclic piperazine having antimicrobial and antifungal activity is used in the preparation of piperazinomycin. The improved Ullmann macrocyclization reaction is conducted on the diketopiperazine. The minor metabolite produced by Streptoverticillium olivoretticuli is separated by the piperazinomycin.

Sequential regioselective nucleophilic substitution reactions of the unsymmetrical p-quinone diimine 3 in the preparation of a dihydropyrroloindole precursor to the left-hand subunit formed the basis of the total syntheses of natural (+)- and ent-(-)-duocarmycin SA. (+)-N-BOC-DSA had the most powerful intrinsic cytotoxic activity of all natural and synthetic allylation subunits explored so far.

Thesynthesis and evaluation of prototypical CDPI3-enediyne and CDPI3-EDTA conjugates as a new class of cleaving agents is discussed. This involved the linkage of CDPI3 to EDTA and an enediyne capable of Bergmann cyclization. Ability to cleave DNA was studied through examination of single and double strand cleavage of supercoiled DNA to form relaxed and linear DNA. Complete cleavage was not detected except at high agent concentration. This was attributed to various contributing factors that included slow Bergman cyclization rates and unproductive cyclization not leading to DNA scission.

An intramolecular Ullmann reaction provides for the macrocyclization of the cycloisodityrosine unit of three bouvardin analogues. The dipeptide, obtained from N-CBZ-3-acetyl-L-tyrosine methyl ester, is coupled with a preformed D-Ala-Ala-N-ME-Tyr-(OMe)-Ala tetrapeptide in a synthetic process capped by a C2-N2 amide bond-fomring macrocyclization to form RA-VII and deoxybouvardin. N29-desmethyl-RA-VII is also prepared via a parallel route. Subsequent bioassays suggest the key role of the tetrapeptide in shaping the cycoisodityrosine conformation and in the bouvardins' bioactivity.

The Diels-Alder reactions of N-sulfonyl alpha,beta-unsaturated imines with unactivated dienophiles were studied. Five substrates were chosen and found to undergo the reaction readily and those with the unactivated dienophile were the most reactive. The hydrolysis of N-sulfonylimine to a ketone was found to be the most significant side reaction. Some substrates provided cycloadducts as 1:1 mixtures of cis and trans isomers while other substrates provided the trans cycloadduct. A strong endo diastereoselectivity was observed for the reaction.

The molecules forming the parent skeletons of CD and DE diphenyl ether 16-membered rings systems of vancomycin and ristocetin were synthesized using the intramolecular Ullmann microcyclization reaction. Results revealed that Ullmann macrocyclization closure of the DE system was faster and gave higher yields compared to the CD system. However, the reaction was inhibited by N-methylation of the amide linking chain. Cyclization conversions increased following alpha-substitution of the linking chain's central amino acid.

The 5-exo-trig aryl radical-alkene cyclization, which enables direct introduction of 3, 3-bis(hydroxymethyl)indoline, is a crucial step in the nine to ten step process leading to the formation of 9a-(chloromethyl)-1,2,9, 9a-tetrahydrocyclopropa(c)benz(e)indol-4-one (C2BI). The N-BOC-C2BI, formed when (C2BI) is incorporated into functional analogs of CC-1065 and duocarmycins, is about 12 times more stable than the CC-1065. The compound is involved in the nucleophilic addition reaction to the minimally substituted cyclopropane carbon.

The optimum use of stable toluenesulfonyl cyanides provides an efficient way of preparing N-sulfonylimines from ketone and aldehyde oximes. The process involves the in situ isomerization of the cyanide into a cyanate and its reaction with the oxime. A study of reaction conditions shows that yields of up to 69% are obtained by using carbon tetrachloride as solvent, triethylamine as tertiary amine base and -20 or 0 degree C as the initial reaction temperature with subsequent warm-up for the rearrangement step. Dichloromethane or diethyl ethermay be used for non-CCl4 soluble substrates.

The presence of a strong electron-withdrawing ethoxycarbonyl group at C-2 enables N-sulfonyl-1-aza-1,3-butadiene to undergo Diels-Alder cycloaddition with dienophiles that leads to the synthesis of the DEF ring system of fredericamycin A. Conducting the reaction under pressure at room temperature avoids the tautomerization that usually occurs at 100 degrees C. Subsequent treatment with 1,8-diazabicyclo(5.4.0)undec-7-ene, deprotonation with lithium diisopropylamide, condensation with 2-cyclopentenone and oxidation with 2,3-dichloro-5,6-dicyanobenzoquinone finally provide the DEF ring system in 60-64% overall yield.

A more direct route to the synthesis of N-tert-butoxycarbonyl derivative of 1,2,9, 9a-tetrahydrocyclopropa(c)benz(e)indol-4-one (N-BOC-CBI) is via condensation of ammonia with 1,3-dihydroxynaphthalene and subsequent N-BOC protection. CBI is an analogue of CC-1065, a potent antitumor drug involved in the minor groove alkylation of DNA. CBI-based agents are more efficient in this respect than the corresponding cyclopropapyrrolindolone (CPI) analogues. The route leads to 5-benzyloxy-3-(tert-butyloxycarbonyl)-1-(hydroxymethyl)- 1, 2-dihydro-3H-benz(e)indole, the immediate precursor of N-BOC-CBI.

The formation of the Wadsworth-Horner-Emmons reagent from the condensation of (1'E, 3'E)-2-methyl-4-(2'-methyl-5'-oxo-1',3'-pentadienyl)-oxazole provides the structure for the stereoselective addition of the C18-C19 trisubstituted olefin. The resulting intermediate leads to the preparation of the C13-C26 lower subunit of rhizoxin. Moreover, the synthesis involves the formation of a condensation intermediate exhibiting relative and absolute stereocontrolled C15-C17 structures which allow the stereoselective assemblage of the rhizoxin C13-C26 lower subunit.

Treatment of phenyl selenoesters with tri-n-butyltin hydride provides acyl radicals that undergo addition reactions with olefins. With electron-poor or radical-stabilizing alkenes, the primary alkyl-, vinyl- and arylacyl radicals react via intermolecular addition faster than competing decarbonylation or reduction. Via intramolecular addition, the reactions are more efficient than those using acid chlorides or phenyl thioesters regardless of the nature (electron-rich or poor or unactivated) of the alkene. The regiochemistry and mechanism of such reactions are also discussed.

ACDPIn and TACDPIn binding agents, which are functionalized derivatives of the N3-tert-butyloxycarbonyl intermediate of CDPI1, present opposing effects on the noncovalent DNA minor groove binding affinity. The peripheral C-5 amino group of ACDPIn creates destabilizing electrostatic interactions which substantially decrease the DNA binding groove affinity. Contrastingly, the C-5 quaternary amine of TACDPIn produces stabilizing electrostatic interactions which strengthen the DNA binding affinity. Moreover, the results have shown that ACDPI3 features selectivity for AT-versus GC-rich DNA and possesses the highest binding constant among the ACDPIn binding agent series.