Reflections on the intriguing occurrence of some recently isolated natural products as racemates and scalemic mixtures.

This review continues our interest in the intriguing reports of a variety of new racemic natural products (at least 11 in the past 4 years). These include the polyphenolic racemate galewone, the polycyclic prenylated acylphloroglucinol garcinielliptone; variecolortide, a combination of an anthraquinone and a isochinulin-type alkaloid; the isoindoline alkaloid irpexine, the new hybrid phenylproanoid asarone; colletopyandione an indolydenepyradione; the enantiomerically enriched (scalemic) neolignans, gardenifolins; and meroterpenoid pabmaragramin in addition to some marine lipids. We also present a recent biomimetic synthesis of the polyketide preuisolactone A; synthesis of the polyketide spiromamakone A, which also corrected the proposed structure of another metabolite as identical to spiromamakone A; and the melicolones A and B.

The enduring legacy of Koji Nakanishi's research on bioorganic chemistry and natural products. Part 1: Isolation, structure determination and mode of action.

In this brief review on Koji Nakanishi's remarkable career in natural products chemistry, we have highlighted a number of his accomplishments that illustrate the broad diversity of his interests. These include the isolation, structure determination, and biological mechanism of action of many natural products including the triterpenoid pristimerin; the diterpenoid ginkgolides; insect and crustacean molting hormones; phytoalexins; the toxic red tide principle brevetoxin; the vanadium tunicate pigments; philanthotoxin from killer wasps; antisickling agents; mitomycin DNA adducts; insect antifeedants; a mitotic hormone, the small molecule fish attractants from the sea anemone; new isolation and purification technologies; molecular chemistry of vision; age-related macular degeneration; and the development of the exciton circular dichroism (CD) chirality method for microscale determination of absolute configuration of natural products and chirality of other chiral molecules and supramolecular assembly.

Pimarane diterpenes: Natural source, stereochemical configuration, and biological activity.

Plants and fungi are seemingly inexhaustible sources of interesting natural products with remarkable structural and biological diversity. One of the most important groups is the terpenes, ubiquitous natural products that are generated by 2 now well-established biosynthetic pathways: the older mevalonate and the more recently discovered 1-deoxyxylulose-5-phosphate. Among the diterpenes, the pimarane diterpenes are a very representative subgroup with several and interesting biological activities resulting from different functional group modifications.

Biomimetic syntheses of racemic natural products.

Racemic natural products are rarely produced in plants and microorganisms and are thought to be the result of nonenzymatic, spontaneous reactions. These compounds are often highly complex with multiple contiguous chiral centers that present a challenge to organic synthesis. Formation of these racemates often occurs by cyclization reactions that can generate multiple stereocenters from achiral precursors.

Circular dichroism analysis of the calicheamicin-DNA interaction revisited.

Calicheamicin, γ, is a remarkable DNA binding-cleaving, enediyne-containing, natural product that exhibits potent antitumor activity. In this study, we used electronic circular dichroism spectroscopy to monitor potential drug-induced DNA conformational changes and DNA induced conformational changes in the calicheamicin aglycone. Three DNA dodecamer sequences were examined: one containing a primary TCCT binding/cleavage site and two dodecamers containing less prominent CTCT and TCTC sites.

Recent Advances in Stereoselective Drug Targeting.

Reviewed here are some recent examples of medically important protein targets for which stereoselective drugs have been identified. These include heat shock protein 90 (Hsp90) inhibitors as anticancer agents; transient receptor potential vanilloid type 1 antagonists as new analgesics; stereospecific inhibition of human mutT homolog MTH1 for cancer treatment; the stereoselective binding of R- and S-propranolol by the α1-acid glycoprotein transporter; metallohelical complexes that are nonpeptide α-helical mimetics that enantioselectively target Aβ amyloid for the treatment of Alzheimer's disease; metallohelical assemblies with promising antimicrobial activity that enantioselectively target DNA of resistant bacteria; nonpeptide α-helical metallohelices that target the DNA of cisplatin-resistant cancer cells; diastereomeric selectivity of phenanthriplatin-guanine adducts; and phenazine biosynthetic enzyme active sites that can host both enantiomers of a racemic ligand simultaneously.

Biological stereoselectivity of atropisomeric natural products and drugs.

Selected examples of natural product and drug atropisomers that exhibit stereoselectivity towards receptor and enzyme targets are reviewed. The atropisomeric preference of the receptors and enzyme binding domains makes these agents attractive molecules for drug development in the treatment of various diseases. Included are commonly recognized atropisomers containing a chiral biaryl axis along with some less common examples of atropisomers without a biaryl axis.

Synthesis of antioxidants for prevention of age-related macular degeneration.

Photooxidation of A2E may be involved in diseases of the macula, and antioxidants could serve as therapeutic agents for these diseases. Inhibitors of A2E photooxidation were prepared by Mannich reaction of the antioxidant quercetin. These compounds contain water-solubilizing amine groups, and several were more potent inhibitors of A2E photooxidation than quercetin.

Plasmonic chiroptical response of silver nanoparticles interacting with chiral supramolecular assemblies.

Silver nanoparticles were prepared in aqueous solutions of chiral supramolecular structures made of chiral molecular building blocks. While these chiral molecules display negligible circular dichroism (CD) as isolated molecules, their stacking produced a significant CD response at room temperature, which could be eliminated by heating to 80 °C due to disordering of the stacks. The chiral stack-plasmon coupling has induced CD at the surface plasmon resonance absorption band of the silver nanoparticles.

Structural and conformational features relevant to the anti-tumor activity of calicheamicin γ 1I.

The structural and conformational features of the potent 10-membered enediyne-containing calicheamicin γ 1I that account for its remarkable DNA site-specific binding and cleavage are reviewed. A variety of spectroscopic and biophysical techniques were used to gain insight into the binding and stereospecific DNA cleavage of this potent antitumor agent. These include gel-shift cleavage assays, atom transfer NMR experiments, drug-DNA conformational studies, circular dichroism, and capillary electrophoresis.

Calicheamicin γ1(I) and phenyl tert-butyl nitrone (PBN): observation of a kinetic isotope effect by an ESR study.

ESR study of enediyne calicheamicin gamma(1)(I) with phenyl tert-butyl nitrone (PBN) gave a significant kinetic isotope effect (k(H)/k(D) = 1.8) for the formation of the phenyl radical PBN monoadducts.

Role of environmental factors on the structure and spectroscopic response of 5'-DNA-porphyrin conjugates caused by changes in the porphyrin-porphyrin interactions.

We have explored the utility, strength, and limitation of through-space exciton-coupled circular dichroism in determination of the secondary structure of optically active chromophoric nanoarrays using the example of end-capped porphyrin- and metalloporphyrin-oligodeoxynucleotide conjugates. We put special emphasis on the explanation of the origin and significance of the distinctive multiple bands in the CD spectra (trisignate and tetrasignate CD bands). Such CD profiles are often observed in chiral aggregates or multichromophoric arrays but have never before been studied in detail.

Synthesis and characterization of water-soluble free-base, zinc and copper porphyrin-oligonucleotide conjugates.

We describe the synthesis and characterization of a series of water-soluble free-base, zinc, and copper porphyrin-oligonucleotide (ODN) conjugates. A non-charged tetraarylporphyrin was directly attached to the 5'-position of thymine via a short amide linker. Such a linker should allow for rigid connection to the adjacent nucleobases, thus increasing the sensitivity for monitoring conformational changes of the ODNs by electronic circular dichroism due to capping effects or ligand binding.

Biochemical and biophysical characterization of inhibitor binding to caspase-3 reveals induced asymmetry.

Activation of the caspase family of cysteine proteases results in the deregulation of cellular homeostasis and apoptosis. This deregulation is a key factor in the development of Alzheimer's disease, Parkinson's disease, and cancer. Thus, the caspases are important drug targets for the therapeutic intervention of a number of pathological states involving inflammation and apoptosis.

Development of an HPLC assay for Staphylococcus aureus sortase: evidence for the formation of the kinetically competent acyl enzyme intermediate.

Many bacterial surface proteins containing an LPXTG motif are anchored to the cell wall peptidoglycan by catalysis with the thiol transpeptidase sortase. The transpeptidation and hydrolysis reactions of sortase have been proposed to proceed through a common acyl enzyme intermediate. The reactions of Staphylococcus aureus sortase with fluorogenic substrate Abz-LPETG-Dnp in the presence or absence of triglycine were characterized in this study to gain additional insight into the kinetic mechanism of sortase.

Spin-trapping of the p-benzyne intermediates from ten-membered enediyne calicheamicin gamma1I.

In the presence of thiols, the ten-membered-ring enediyne calicheamicin gamma1I generates a p-benzyne biradical that initiates oxidative cleavage of double-stranded DNA. Application of spin-trapping has successfully provided ESR and mass spectroscopic evidence for the formation of the monoadducts with phenyl tert-butyl nitrone (PBN). [reaction: see text].

Porphyrins conjugated to DNA as CD reporters of the salt-induced B to Z-DNA transition.

The porphyrin chromophore incorporated at the 5'-position of an oligonucleotide allows the simultaneous detection of the B- to Z-DNA transition via the porphyrin Soret band circular dichroism exciton couplet signal around 420 nm and the oligonucleotide CD region below 300 nm, at micromolar concentrations.

Structure and chiroptical properties of supramolecular flower pigments.

Research over the last 30 years has shown that at physiological concentrations of ca. 5 x 10(-3) M, flower pigments composed of anthocyanins, either alone or complexed with flavone copigments, and frequently with metals, are self-assembled into non-covalent, chiral supramolecular complexes. This serves several biological functions including color stability, protection against UV radiation and provision for specific colors to attract insects for pollination.

5'-Porphyrin-oligonucleotide conjugates: neutral porphyrin-DNA interactions.

[chemical reaction: see text]. Incorporation of hydrophilic tetraarylporphyrin phosphoramidites into the 5'-termimus of the DNA as well as noncharged porphyrin-DNA interactions have been studied. Porphyrin-modified oligonucleotides show lower melting temperatures than their unmodified analogues.

Theoretical simulation of the electronic circular dichroism spectrum of calicheamicin.

The aglycon, or so-called 'warhead' portion, of several potent 10-membered ring enediyne antitumor antibiotics contain dienonecarbamate and enediyne chromophores in an unusual bicyclic ring structure in which these two subunits are essentially orthogonal to each other. The circular dichroism (CD) spectra of the calicheamicin, esperamicin, and shisijimicin A families, all of which contain this bicyclic ring system, exhibit a characteristic negative exciton coupled CD at about 310 and 270 nm. This signature CD feature suggested the absolute stereochemical relationship between these chromophores as originally assigned and which was later confirmed by stereospecific total synthesis.

Probing the interaction of HTI-286 with tubulin using a stilbene analogue.

HTI-286 is a synthetic analogue of the natural product hemiasterlin. HTI-286 is a potent antitumor agent that induces tubulin oligomerization. To investigate the binding stoichiometry and the binding site during this ligand-induced tubulin association, we synthesized an analogue of HTI-286 containing the chromophore stilbene.

Evaluation of fluorescence-based thermal shift assays for hit identification in drug discovery.

The fluorescence-based thermal shift assay is a general method for identification of inhibitors of target proteins from compound libraries. Using an environmentally sensitive fluorescent dye to monitor protein thermal unfolding, the ligand-binding affinity can be assessed from the shift of the unfolding temperature (Delta Tm) obtained in the presence of ligands relative to that obtained in the absence of ligands. In this article, we report that the thermal shift assay can be conducted in an inexpensive, commercially available device for temperature control and fluorescence detection.