The first crystal structure of a drug (daunomycin) bound to a parallel-stranded intermolecular telomeric G4 quadruplex (d(TGGGGT)4) has been determined to high resolution. A planar assemblage of three daunomycin molecules stacks onto the 5' end of the G4 column, with the daunosamine substituents occupying three of the four quadruplex grooves. The surface area of the terminal G-quartet in this parallel DNA quadruplex, presently occupied by three daunomycins, is sufficiently large that it could easily accommodate other potential telomerase inhibitors such as substituted porphyrins or telomestatin.
The sponge Darwinella sp, contains the known compounds ambliofuran (4) and aplysulphurin (3), and the new compound tetrahydroaplysulphurin-1 (5). Daminella oxeata collected from various locations around New Zealand, contains aplysulphurin (3) and the new compounds tetrahydroaplysulphurins-1 (5), -2 (6), and -3 (7). Dendrilla rosea which is morphologically similar to the Daminella sp. above, contains the known compounds ambliofuran (4), aplyroseols-l (8), -2 (9), -3 (lo), -5 (1 l), -6 (12), and -7 (15), as well as the new compounds dendrillol-1 (13), dendrillol-2 (14), dendrillol-3 (17) and dendrillol-4 (18). The structure of dendrillol-l (13) has been confirmed by a single-crystal X-ray determination.Contrary to the previous report,' re-investigation of freeze-dried Darwinella sp. collected from the same locality as that of the previous study, revealed no trace of aplysillin (1) after detailed examination of a hexane extract by column chromatography * Structures (5), (6) and (7) represent relative stereostructures only.
Reaction between the cationic iridacyclopentadiene complex [Ir(C4H4)(NCMe)(CO)(PPh3)2][CF3SO3] (1) and methylpropiolate produces the cationic iridabenzofuran [Ir(C7H5O{OMe-7})(CO)(PPh3)2][CF3SO3] (2) in high yield. On treatment of 2 with chloride, the carbonyl ligand is displaced and the corresponding neutral iridabenzofuran Ir(C7H5O{OMe-7})Cl(PPh3)2 (3) is formed. The fused metallacyclic rings of the iridabenzofurans 2 and 3 bear only one substituent (OMe), and therefore these compounds are well suited for studies of electrophilic aromatic substitution reactions. Bromination of cationic 2 with pyridinium tribromide proceeds to give the monobrominated iridabenzofuran [Ir(C7H5O{OMe-7}{Br-6})(CO)(PPh3)2][CF3SO3] (4) exclusively. Bromination of neutral 3 with the same reagent gives the dibrominated iridabenzofuran Ir(C7H5O{OMe-7}{Br-6}{Br-2})Br(PPh3)2 (5) exclusively. Treatment of compound 3 with mercury(II) trifluoroacetate followed by excess bromide (to displace coordinated trifluoroacetate) produces the trimercurated iridabenzofuran Ir(C7H5O{OMe-7}{HgBr-6}{HgBr-4}{HgBr-2})Br(PPh3)2 (6). The three Hg−C bonds in 6 are readily cleaved on addition of pyridinium tribromide, and the resulting product is the tribrominated iridabenzofuran Ir(C7H5O{OMe-7}{Br-6}{Br-4}{Br-2})Br(PPh3)2 (7). These regioselective mono-, di-, and trifunctionalization reactions of iridabenzofurans have been studied by DFT calculations, and the derived condensed Fukui functions have been used to rationalize the preferred sites for electrophilic attack. The crystal structures of 2−7 have been obtained.
Reaction between the diphenylacetylene complex Os(PhCtCPh)(CS)(PPh 3 ) 2 (1) and two molecules of HCtCCO 2 Me leads to a very stable, blue, osmabicylic complex with osmium at a bridgehead position. One way to consider this complex is as a metalla-aromatic molecule, viz., the osmabenzofuran Os-[C 7 H 2 O(OMe-7)(CO 2 Me-4)(Ph-1)(Ph-2)](CS)(PPh 3 ) 2 (2). The bicyclic ring system is remarkably robust, and heating this compound in ethanol at reflux with aqueous HCl effects only a transesterification of the ester function in the six-membered ring (at the 4-position), forming Os 2) with pyridinium tribromide effects bromination in the five-membered ring of the osmabenzofuran at the 6-position to form Os[C 7 HO(OMe-7)(Br-6)(CO 2 Me-4)(Ph-1)(Ph-2)](CS)(PPh 3 ) 2 (4). Crystal structure determinations of 2, 3, and 4 confirm the osmabicyclic structure of each compound. Treatment of complex 2 with anhydrous trifluoroacetic acid results in protonation at carbon atom 6 to form the cationic, tethered osmabenzene [Os[C 5 H(CH 2 CO 2 Me-5)(CO 2 Me-4)(Ph-1)(Ph-2)](CS)(PPh 3 ) 2 ]CF 3 CO 2 (5). This osmabenzene cation has also been isolated as the tri-iodide salt [Os[C 5 H(CH 2 CO 2 Me-5)(CO 2 Me-4)(Ph-1)(Ph-2)](CS)-(PPh 3 ) 2 ]I 3 (6) and the crystal structure for this complex obtained. The spectroscopic and the structural data for 2, 3, and 4 give support for the osmabenzofuran formulation for these compounds. The spectroscopic data for 5 and 6 and the structural data for 6 support the tethered osmabenzene formulation for these two compounds.
Crystal structures are reported of complexes of two novel furan derivatives of berenil with alkyl benzamidine groups bound to the DNA sequence d(CGCGAATTCGCG)2. They have both been determined to 2.2 A resolution and refined to R factors of 16.9% and 18.6%. In both structures the alkyl substituents, cyclopropyl and isopropyl, are found to be orientated away from the floor of the minor groove. The drugs are located in the minor groove by two strong amidinium hydrogen bonds, to the O2 of the thymines situated at the 5' and 3' ends of the AT-rich region. The isopropyl-substituted derivative has a tight hydrogen-bonded water network in the minor groove at one amidine site, which alters the orientation of the isopropyl substituent. This compound has superior DNA-binding properties and activity against Pneumocystis carinii and Cryptosporidium parvum infections in vivo compared to the cyclopropyl derivative, which in turn is superior to the parent furan compound. We suggest that the nature and extent of the interactions of these compounds in the DNA minor groove play an important role in these activities, possibly in conjunction with a DNA-binding protein. The overall effect of these alkyl benzamidine substitutions is to increase the binding of the drugs to the minor groove.
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