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Oleamide is a sleep-inducing lipid originally isolated from the cerebrospinal fluid of sleep-deprived cats. Oleamide was found to potently and selectively inactivate gap junction-mediated communication between rat glial cells. In contrast, oleamide had no effect on mechanically stimulated calcium wave transmission in this same cell type. Other chemical compounds traditionally used as inhibitors of gap junctional communication, like heptanol and 18beta-glycyrrhetinic acid, blocked not only gap junctional communication but also intercellular calcium signaling. Given the central role for intercellular small molecule and electrical signaling in central nervous system function, oleamide- induced inactivation of glial cell gap junction channels may serve to regulate communication between brain cells, and in doing so, may influence higher order neuronal events like sleep induction.

Research has been conducted on glycinamide ribonucleotide transformylase. The crystal structure of the trifuntional protein's human ribonucleotide transformylase component has been investigated at different pH values in complex with its substrate, and the details are reported.

Research has been conducted on anhydrolycorinone. The synthesis of this compound carried out via sequential intramolecular Doels-Alder reactions of the substituted 2-amino-1,3,4-oxadiazole is described.

Research has been conducted on the glycinamide ribonucleotide transformylase's multisubstrate adduct inhibitors. The crystal structure of the Escherichia coli glycinamide ribonucleotide transformylase has been determined to ascertain the nature of the time-dependent enzyme inhibition and the results are presented.

Research has been conducted on the 132 (+)-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (CBI) analogues of CC-1065 and the duocarmycins that contain dimeric monocyclic, bicyclic and tricyclic heteroaromatic DNA-binding domain replacement. The solution-phase, parallel synthesis and evaluation of the library of these compounds have been carried out and discussed.

Research has been conducted on the series of C3-substituted 1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (CBI) analogues of CC-1065 and duocarmycin alkylation subunits. The synthesis and evaluation of these compounds have been carried out and investigated.

The preparation and evaluation of the 5-methoxycarbonyl-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one is reported. The comparison results of the analogues that incorporate this alkylation subunit are presented.

Results demonstrate a solution-phase synthesis of an analogue of triostin A by substituting D-serine amino acid with D-beta-aminoalanine in the natural antibiotic. Data reveal that this step facilitates solution-phase extraction and purification of the analogue.

Results reveal that the C6 methoxycarbonyl group in duocarmycin SA increases the rate and efficiency of DNA alkylation, whereas the C7 slows the reaction. The increased activity of C6 is due to its extended length for greater DNA binding. Removal of the C6 methyl ester subunit decreases the alkylation rate.

Results show that CPyI analogues possess identical DNA alkylation sequence selectivity and DNA alkylation efficiencies and are activted by metal cations. Data further suggest that even with structural changes in the alkylation subunit, CPyI analogues retain their potent cytotoxic activity.

The total synthesis of the marine natural product ningalin B uses a heteroaromatic azadiene Diels-Alder reaction, which assembles the substituents onto a six-membered 1,2-diazene core followed by a reductive ring contraction reaction to form pyrrole. Data indicate that the reaction involves a [4+2] cycloaddition of 1,2,4,5-tetrazine to the electron-rich alkyne.

The scanning and deletion synthesis of two libraries of 120 Arg-Gly-Asp mimetic compounds reveal the active constituents in the mixture combinatorial libraries in a cytotoxic assay.

Inhibitory properties of Escherichia coli Tfase have been determined by means of crystal structure study of Escherichia coli GAR Tfase. The presence of the hydrated aldehyde has been confirned in solution by (super)13 C - (super)1 H NMR spectroscopy.

Convergent solution-phase combinatorial synthesis is discussed relative to increasing diversity via rigid biaryl and diarylacetylene couplings. Solution-phase synthesis of iminodiacetic acid diamide libraries linked to aryl iodides and palladium-catalyzed dimerization has been studied. Mixtures with 64,980 components have been produced in four steps from N-BOC-iminodiacetic acid anhydride and 21 starting materials that are readily available. Sequential Stille couplings and biaryl formation are used in the synthesis.

Solvolysis pH-rate profiles of two reactive CC-1065/duocarmycin alkylation subunit analogues, N-BOC-CBQ and N-BOC-CNA, shows a reactivity ranging from pH 2 to 12. The study also demonstrated a progressively diminished vinylogous amide conjugation that leads to a corresponding increase in reactivity to conformations proposed by the DNA-bound CC1065. The results indicate that the observed CC-1065 and duocarmycin DNA alkylation reaction at pH 7.4 is not an acid-catalyzed reaction.

Analogue 7 of the duocarmycins and CC-1065 manifested increased solvolysis reactivity at pH 3. Theincrease, which is consistent with the increased electron-withdrawing properties and conjugation of thioamides relative to amides, can be attributed to a diminished vinylogous amide stabilization of the reacting alkylation subunit. Amidine 6, which underwent preferential N2 amidine linkage hydrolysis, was found to be more unstable than 7 despite the diminished electron-withdrawing properties.

A study was conducted to analyze an approach to the solution phase preparation of biaryl libraries from iodoarenes. Pd-C was utilized as a readily available supported catalyst. The isolation and purification of small library mixtures were discussed. Results indicated that the direct convergent solution phase dimerization of combinatorially assembled iodoarene building blocks supports an effective and rapid pathway to symmetrical and unsymmetrical structures.

A carbocyclic C-ring analogue of the alkylation subunits of CC-1065 and duocarmycins, 1,2,9,9a-tetrahydro-1H-cyclopropa(C)benz(e)inden-4-one, was synthesized, a key step of which was implementation of the intramolecular Heck reaction. Results of an examination of its solvolysis reactivity, regioselectivity and mechanism showed that reactivity increased by 3,200 times with the removal of the nitrogen and resulting vinylogous amide stabilization, while reversing the inherent regioselectivity. However, it left the S(sub N)2 reaction mechanism unaltered.

The synthesis and evaluation of CC-2065 and duocarmycin analogues incorporating the iso-Cl and iso-CBl alkylation subunits are described. The method was founded on a directed ortho metalation of an appropriately functionalized benzene or naphthalene precursor to regiospecifically install iodine at the C-2 position. Agents were observed to exhibit potent cytotoxic activity that correlates with their inherent reactivity which is consistent with previous studies.

A novel method of synthesizing a seven-membered C-ring analog (CNA) of the alkylation subunits of CC-1065 and the duocarmycins was designed through implementation of an alternative intramolecular Heck reaction. The procedure featured the use of palladium acetate as catalyst and 1,3-dihydronaphthalene as the starting material. It was indicated that the ground state destabilization fo the substrate activated the reagent for a rate determining SN2 nucleophilic addition.

The synthesis of fully substituted vancomycin with two 16-membered biaryl ether ring systmes (CD and DE) was reported. A potential solution to the control of the atropisomer stereochemistry was also proposed. It was observed that closure to form the CD ring system provided a 1:1 mixture of atropisomers, while closure of the DE ring system showed a slight preference for the natural atropisomer.

The characteristics of intramolecular nucleophilic aromatic substitution reactions were analyzed during the synthesis of (9R, 12S)- and (9S, 12S)-cycloisodityrosine and their N-methyl derivatives. The benzylic bromination of 2-fluoro-4-methylnitrobenzene by 1,3-dibromo-5,5,-dimethylhydantoin led to the synthesis of (S)- and (R)-3-fluoro-4-nitrophenylalanine methyl ester. Furthermore, 14-membered ring macrocyclization reactions led to formation of a biaryl ether by smooth 14-membered ring closure.

The relative and absolute chemistry of the potent antitumor antibiotic fostriecin have been determined. The results showed an absolute chemistry of 5R, 8R, 9R, 11R. A syn-diol stereochemical relationship between C8 and C9 and an anti-diol stereochemical relationship between C9 and C11 were established by 2D 1H-1H NMR NOE spectroscopy.

The synthesis of 7-cyano-1,2,9,9a-tetrahydrocyclopropa(c)benz(e)indol-4-one, (CCBI) helps to establish the electronic effect on functional reactivity of an agent. The nitrile substituent at C7 in N-BOC-CCBI has a small electronic effect on functional reactivity according to Hammett quantization. The mechanism involves rapid proton exchange and nucleophilic addition to least hindered carbon in cyclopropane is the rate determining step. Likewise, the positioning of nucleophile adenine N3 is the rate determining step in DNA alkylation, which does not affect DNA alkylation selectivity.

The Sharpless asymmetric dihydroxylation of a substituted styrene produces derivatives of (R)-(3,4,5-trihydroxyphenyl)glycine. The formation of styrene involves methylation of 3,4,5-trihydroxybenzoate, formation of an aldehyde and a Wittig reaction. The oxidation of the styrene primary alcohol yields the derivative. CBZ deprotection, or CBZ deprotection and N-BOC protection of the free amino acid of the derivative yields other derivatives. (R)-(3,4,5-trihydroxyphenyl)glycine is present in the bicyclic ring of glycopeptide antibiotics such as vancomycin.

The synthesis and characterization of 7-methoxy-1,2,9,9a-tetrahydrocyclopropa(c)benz(e)indole-4-one (MCB) are described. The core structure of the MCBI alkylation unit has been formed via modified Stobbe condensation/Friedel-Crafts acylation to generate the functionalized naphthalene precursors. Subsequent 5-exo-trig aryl radical-alkene cyclization completes the preparation of the 1,2-dihydro-3H-benz(ene)indole skeleton and final Ar-3' alkylation to introduce the cyclopropane. The reaction mechanism for the synthesis is outlined.

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%.

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.

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.

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.

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 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.

Research describes the asymmetric synthesis of L-threo-FmocNH-beta-OH-Asn(trt)-OBn and other protected asparagine residues via Sharpless asymmetric aminohydroxylation reaction.

The synthesis of 3-hydroxyquinoline-2-carboxylates is described. The method involves the Friedlander condensation of O-methyloxime with 2-aminobenzaldehydes. The quinoline Friedland condensation products produced as carboxylic acids are converted to the corresponding methyl esters. Benzyl deprotection of the methyl esters provides the corresponding methyl 3-hydroxyquinoline-2-carboxylates.

Total synthesis of phostriecin, the assignment of its relative and absolute stereochemistry and the resultant structural reassignment of the natural product which previously represented as sultriecin, a phosphate versus sulfate monoester, are detailed. The synthesis and evaluation of a series of key synthetic analogues that highlights the importance of the natural product phosphate monoester, the [alpha],[beta]-unsaturated lactone (12-fold), and the hydrophobic Z,Z,E-triene tail (C12?C22, ca. 200-fold) including the unique importance of its unsaturation are also detailed.

The synthesis of the tri- and tetrapeptide S subunits of bleomycin A2 was undertaken. Tripeptide S was generated from the precursor (2S,3S, 4R)-N-(tert-butoxycarbonyl)-4-amino-3-hydroxy-2-methylpentanoic acid via a syn aldol addition reaction followed by methyl ester formation, N-BOC deprotection, S-methylation and acid-catalyzed deprotection. Tetrapeptide S was also derived in an analogous manner from the same precursor.

Inverse electron demand Diels-Alder cycloaddition of 1,1-diaminoethane with 2,4,6-tris(ethoxycarbonyl)-1,3, 5-triazine provides the pyrimidine nucleus for the synthesis of desacetamido P-3A, the simplest member of the bleomycin antitumor drugs. The synthetic study of P-3A seeks to prove that it is not the C2-acetamido chain but the pyrimidine nucleus itself that is involved in the chelation of copper(II). The chelation site indicates the point of O2 activation and DNA cleavage thought to be responsible for bleomycin's antitumor activity.

The synthesis of N(29)-desmethyl RA-VII leads to a study of its structure and conformation in relation to its antitumor activity. The process, involving an intramolecular Ullmann macrocyclization as a key step, is based on a tyrosine, a phenylalanine and a tetrapeptide as main substrates. Subsequent NMR studies, which include those of two key intermediates, suggest that it is the tetrapeptide within the 18-membered ring that induces a rigid, normally inaccessible conformation within the 14-membered cycloisodityrosine ring. Bioassay results on the three synthesized species support this analysis.

Two new unsymmetrical 1,2,4,5-tetrazines, 3-methylsulfinyl-6-methylthio-1,2,4,5-tetrazine and 3-(benzyloxycarbonyl)amino-6-methylsulfinyl-1,2,4,5-tetrazine, were prepared, and the scope of their participation in intermolecular inverse electron demand Diels-Alder reactions was defined. As anticipated, sulfoxides 1,2,4,5-tetrazines, 3-methylsulfinyl-6-methylthio-1,2,4,5-tetrazine and 3-(benzyloxycarbonyl)amino-6-methylsulfinyl-1,2,4,5-tetrazine display a reactivity that is substantially greater than that of their corresponding sulfides, derived from their enhanced electron-deficient character and resulting in a wider range of potential dienophile choices or the use of milder reaction conditions.

A study applies the density functional theory at the B3LYP/6-311+G(d,p)//B3LYP/6-31G(d) level to examine the energetics of alpha,betau versus beta,gamma-unsaturation for some common organic functional groups. The relative stabilities of allyl-X and 1-propenyl-X isomers have been computed and the results compared to available experimental data.

An effective asymmetric synthesis of the key CBI precursors, 1,2,9,9a- tetrahydrocyclopropa[c]benzo[e]indol-4-one (CBI) analogue is developed that provides the optically active intermediates in sufficient optical purities.

Details regarding eight-step synthesis and, the evaluation of 1,2,9,9a-tetrahydrocyclopropa[c] benz [e] -3-azaindol-4-one (CBA) and its derivatives containing an aza variant of the CC-1065/duocarmycin alkylation are given.

Research has been conducted on isochrysohermidin, the DNA cross-linking agent's alkylating subunit. The synthesis of this subunit and its incorporation into conjugates with distamycin A are described.