Cytotoxicity, crosslinking and biological activity of three mitomycins.

While interstrand crosslinks (ICLs) have been considered as one type of DNA damage in the past, there is mounting evidence suggesting that these highly cytotoxic lesions are processed differently by the cellular machinery depending upon the ICL structure. In this study, we examined the crosslinking ability of three mitomycins, the structure of the ICLs they produce and the cytotoxicity of the drugs toward three different cell lines. The drugs are: mitomycin C (1), decarbamoylmitomycin C (2), and a mitomycin-conjugate (3) whose mitosane moiety is linked to a N-methylpyrrole carboxamide.

A role of flavonoids in cytochrome c-cardiolipin interactions.

The processes preceding the detachment of cytochrome c (cyt c) from the inner mitochondrial membrane in intrinsic apoptosis involve peroxidation of cardiolipin (CL) catalyzed by cyt c-CL complex. In the present work, we studied the effect of 17 dietary flavonoids on the peroxidase activity of cyt c bound to liposomes. Specifically, we explored the relationship between peroxidase activity and flavonoids' (1) potential to modulate cyt c unfolding, (2) effect on the oxidation state of heme iron, (3) membrane permeability, (4) membrane binding energy, and (5) structure.

Acetone promoted 1,4-migration of an alkoxycarbonyl group on a syn-1,2-diamine.

A 2-protected cis-amino mitosene undergoes an irreversible acetone promoted isomerization and converts to the 1-isomer. Kinetic studies and DFT calculations of the reaction are reported. An organocatalytic mechanism is proposed, involving a covalent intermediate formed by reaction of the mitosene and acetone.

Synthesis of Mitomycin C and Decarbamoylmitomycin C N(2) deoxyguanosine-adducts.

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.

Synthesis of a major mitomycin C DNA adduct via a triaminomitosene.

We report here the synthesis of two amino precursors for the production of mitomycin C and 10-decarbamoylmitomycin C DNA adducts with opposite stereochemistry at C-1. The triamino mitosene precursors were synthesized in 5 steps from mitomycin C. In addition synthesis of the major mitomycin C-DNA adduct has been accomplished via coupling of a triaminomitosene with 2-fluoro-O(6)-(2-p-nitrophenylethyl)deoxyinosine followed by deprotection at the N(2) and O(6) positions.

Theoretical studies of the anti-tumor drug FR900482.

Hartree-Fock and density functional theory (B3LYP) calculations were applied to the study of the anti-tumor drug FR900482 and some of its analogs. Optimum geometries were obtained and it was found that the most stable conformations feature the N-H bond of the aziridine ring nitrogen "down" and the oxygen bridge and aziridine nitrogen "up". It was also found that the analog containing NH(2) (in place of the -CHO of the natural product) is the most prone to oxidation.

Amino acid alanine reactivity with the fingerprint reagent ninhydrin. A detailed ab initio computational study.

Ninhydrin is one of the most widely used reagents for chemical development of fingerprints on porous surfaces. The detection is based on the reaction of ninhydrin with a monoacidic component of the fingerprint to form an intensively colored compound named Ruhemann's Purple. A computational study of the mechanisms and reaction energetics of the formation of Ruhemann's Purple from ninhydrin and alanine is presented.

Theoretical studies of the reduction reaction of the anti-tumor drug FR900482.

A number of analogs of the anti-tumor drug FR900482 have been investigated with quantum chemical calculations, at the HF/6-31G(d,p) and B3LYP levels from the point of view of their energy, optimum geometry and the energetics of the reduction reaction. It was found that the parent molecule is the most prone to reduction, followed closely by fluorine-containing analogs.

An ab initio study of the guanidinium groups in saxitoxin.

Quantum chemical (Hartree-Fock) calculations were performed on neutral and protonated saxitoxin in order to obtain optimum geometries, rotational energy barriers for the guanidinium ions and proton affinities. For comparison purposes, as model compounds, guanidinium systems in five and six membered rings were also investigated. In addition, DFT (B3LYP) calculations with the 6-31G** basis set were performed and the sodium affinities of the guanidinium groups in saxitoxin were obtained.

An ab initio study of di- and trifluorobenzene-benzene complexes as relevant to carbonic anhydrase II-drug interactions.

Ab initio calculations at the MP2/6-31G* level have shown that variously substituted di- and trifluorobenzenes form non-covalent complexes with benzene that adopt either aromatic-aromatic or H--F binding, the choice being determined by the pattern of fluorination. The binding energies of these structures are from 3.4 to 4.

The role of salt bridge formation in glucagon: an experimental and theoretical study of glucagon analogs and peptide fragments of glucagon.

Background: Glucagon is a 29-residue peptide produced in the alpha cells of the pancreas that interacts with hepatic receptors to stimulate glucose production and release, via a cAMP-mediated pathway. Type 2 diabetes patients may have an excess of glucagon and, as such, glucagon antagonists might serve as diabetes drugs. The antagonists that bind to the glucagon receptor but do not exhibit activity could be analogs of glucagon.

Ab initio studies of the reaction of hydrogen transfer from DNA to the calicheamicinone diradical.

Background: The biological activity of enediyne chemotherapeutic (anti-cancer) agents is attributed to their ability to cleave duplex DNA. Part of the reaction of cleavage is the abstraction of hydrogens from the deoxyribose moiety of DNA by the biradical formed via a Bergman rearrangement.

Methods: The mechanism of the reaction of abstraction of two hydrogen atoms from two deoxyribophosphate molecules by the calicheamicinone biradical is studied with ab initio calculations at Hartree-Fock and post-Hartree-Fock level.

Examination of the reduced affinity of the thymidylate synthase G52S mutation for FdUMP by ab initio and semi-empirical studies.

Background: The G52S mutation in the Arg50 loop of thymidylate synthase leads to decreased binding of FdUMP. It has been suggested that the mutation affects the Arg50 residue (within the Arg50 loop) responsible for binding the phosphate of FdUMP. The binding of the methylguanidinium moiety as a model for Arg50 to a methylphosphate entity as a model for FdUMP was investigated with theoretical calculations, as well as the structure of the Arg50-Thr51-Gly52 tripeptide in comparison with the Arg50-Thr51-Ser52 tripeptide.

Semi-empirical, ab initio and molecular modeling studies on the DNA binding of a calicheamicinone-polyamide conjugate.

AM1 semi-empirical and ab initio calculations were performed on certain synthetic polyamide conjugates of the aglycone of the minor groove binding antibiotic calicheamicin. Geometry optimized conformations and heats of formation were obtained. The binding of the optimized conformations of the drug to both alternating and non-alternating (AT)n and to (G)n x (C)n sequences were studied and the energies of binding were compared to each other.

Ab initio calculations on (-)-calicheamicinone and some of its reactions involved in its activation and interaction with DNA.

Ab initio calculations were performed on (-)-calicheamicinone, and on the product (Z or E) of the Michael addition via a reaction with methanethiol. It is found that the sulfur moiety position versus the rest of the molecule is quite flexible. The Michael adduct featuring the carbamate group E to the sulfur moiety is more stable than the Z isomer.

Models of F.H contacts relevant to the binding of fluoroaromatic inhibitors to carbonic anhydrase II.

[formula: see text] Complexes formed between fluorobenzene and N-methylformamide or benzene have been used as models of the interaction of fluoroaromatic drugs with carbonic anhydrase II. These structures have been investigated via ab initio and density functional methods, including HF, B3LYP, and MP2 procedures. The results of the calculations are consistent with the hypothesis, suggested originally by experimental X-ray crystal structures of the drug-receptor complexes, that favorable fluorine-hydrogen interactions affect binding affinity.

Ab initio studies of some amino acid residue complexes with 4-mercaptopyridine as a model for thymitaq (AG337), an inhibitor of thymidylate synthase.

The complex formed by isopentane, as a model for the isoleucine residue present in the wild-type thymidylate synthase, with 4-mercaptopyridine as a fragment of the thymidylate synthase inhibitor Thymitaq (AG337) is investigated with ab initio quantum chemical calculations at Hartree-Fock and MP2 levels, using the 3-21G* basis set. The binding energy is compared with the binding energies of 4-mercaptopyridine with amino acid residues found in mutant thymidylate synthase enzymes. As compared with isoleucine, alanine and glycine do not show binding, in agreement with enzyme-inhibition results.

Theoretical studies employing an ab initio and molecular modeling combination method on the DNA binding of bis-benzimidazoles designed for bioreductive activation.

Ab initio calculations (Hartree-Fock) using the 3-21G and the STO-3G Gaussian basis sets were performed on synthetic analogues of the minor groove binding bis-benzimidazole Hoechst 33258 designed to be subject to bioreductive activation. Such compounds have been shown experimentally to react with DNA to exhibit sequence dependent inhibition of human placental helicase and display significant anticancer properties. Geometry optimized conformations and energies were derived.

Theoretical studies using an ab initio and molecular modelling combination method on the binding of sequence recognition altered bis-benzimidazoles to the minor groove of DNA.

Ab initio calculations (Hartree-Fock) using the 3-21G and the STO-3G Gaussian basis sets were performed on synthetic analogues of the minor groove binding bis-benzimidazole Hoechst 33258 designed to exhibit altered sequence recognition. Geometry optimized conformations, energies and distribution of electrostatic charges within the molecule were derived. The binding of the optimized conformations of the drug to both alternating and non-alternating (AT)n and (GC)n sequences were studied.

Cortisol, high cortisol diseases and anti-cortisol therapy.

Elevated cortisol is found in many diseases, including infectious, aging-related, depression and depression-associated conditions; even in some with no known origin, and no known therapy. While it was initially thought that 'high cortisol' is the result of these diseases, there is mounting evidence to the contrary, namely, that high cortisol actually plays a major role in inducing them, opening the possibility that anti-cortisol drugs might represent a new beneficial therapy. Evidence is here presented, showing that the use of anti-cortisol drugs has already induced beneficial results in conditions ranging from AIDS to depression.

Quantum chemical studies employing an ab initio combination approach on the binding of the bis-benzimidazole Hoechst 33258 to the minor groove of DNA.

Ab initio calculations (Hartree-Fock) using the 3-21G and the STO-3G Gaussian basis sets were performed on the sequence selective minor groove binding bis-benzimidazole Hoechst 33258. Geometry optimized conformations, energies and distribution of electrostatic charges within the molecule were derived. The binding of the optimized conformations of the drug to both alternating and non-alternating (AT)n sequences was studied.

Ab initio studies of 2,4-diamino triazine and its complexes with ligands: a model for inhibitor-active site interactions of dihydrofolate reductase.

The protonation energies of 2,4-diamino triazine, an inhibitor of the therapeutic target dihydrofolate reductase, has been calculated using ab initio (Hartree-Fock) calculations. It is found that N1 (see Fig. 1) exhibits the highest proton affinity (261.

Quantum chemical and molecular mechanics studies on the binding of stereoisomers of the oligopeptide antibiotics amidinomycin and noformycin to the minor groove of B-DNA.

Ab initio calculations (Hartree-Fock) using the 6-31G basis set have been performed on two chiral oligopeptide antitumor antibiotics amidinomycin 5 and noformycin 6. The latter are DNA minor groove binding agents related to the A.T recognizing netropsin 4 and distamycin 3 but, unlike the latter, bear stereocenters (two for 5 and one for 6) that may be expected to affect binding to the B-DNA receptor.

Ab initio studies of aromatic-aromatic and aromatic-polar interactions in the binding of substrate and inhibitor to dihydrofolate reductase.

Aromatic-aromatic and aromatic-polar interactions are investigated by performing ab initio Hartree-Fock calculations. Binding energies and optimum distances between subsystems are obtained. It is found that the binding energy between two benzene rings is of 3.

Amide isosteres of lexitropsins: synthesis, DNA binding characteristics and sequence selectivity of thioformyldistamycin.

The synthesis and properties of an amide isostere of the antibiotic distamycin, thioformyldistamycin 3 is described. Compound 3 exists predominantly in the E conformation of the thioamide group in freshly prepared DMSO solution but is converted into the Z form, predicted by molecular mechanics to be more stable, on standing for 24 h. The coalescence temperature in DMSO is 110 degrees C by 1H-NMR.