Unexpected Reactivity of the 9-Aminoacridine Chromophore in Guanidylation Reactions

The 9-aminoacridine chromophore is an important building block of DNA-targeted chemotherapeutic agents. The success of 1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea as a carrier group in cytotoxic platinum−intercalator conjugates prompted us to explore the synthesis of an analogous guanidine-functionalized acridine. In a successful effort to generate such a derivative, various methods of guanidylation were employed, which demonstrate that the acridine C9−N9 linkage is highly susceptible to electrophilic and nucleophilic attack. The newly established reactivities provide efficient pathways to novel cyclic and spirocyclic acridine derivatives

Unexpected Reactivity of the 9-Aminoacridine Chromophore in Guanidylation Reactions

The 9-aminoacridine chromophore is an important building block of DNA-targeted chemotherapeutic agents. The success of 1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea as a carrier group in cytotoxic platinum−intercalator conjugates prompted us to explore the synthesis of an analogous guanidine-functionalized acridine. In a successful effort to generate such a derivative, various methods of guanidylation were employed, which demonstrate that the acridine C9−N9 linkage is highly susceptible to electrophilic and nucleophilic attack. The newly established reactivities provide efficient pathways to novel cyclic and spirocyclic acridine derivatives

Assembly of Hybrid Inorganic−Organic Materials from Octahedral Nb₆ Clusters and Metal Complexes

The octahedral edge-bridged niobium cyano-chloride cluster [Nb6Cl12(CN)6]4- and the [Mn(salen)]+ metal complex have been used as building units to prepare solid-state materials with extended frameworks at room temperature through self-assembly processes. Three materials with different dimensionalities were prepared and characterized:  (Me4N)4[Nb6Cl12(CN)6]·2MeOH (1) (0D), (Me4N)2[Mn(salen)]2[Nb6Cl12(CN)6] (2) (2D), and (Et4N)2[Mn(salen)(MeOH)]2[Nb6Cl12(CN)6]·2MeOH (3) (1D). 1 was used as cluster precursor for the preparation of 2 and 3. The framework dimensionality seems to be affected by the size of the template-counterion used. Single-crystal X-ray analysis revealed that 1 is based on discrete [Nb6Cl12(CN)6]4- separated by (Me4N)+ and MeOH molecules. 2 has a two-dimensional framework, in which each layer is formed by [Nb6Cl12(CN)6]4- clusters connected through four cyanide ligands to four different [Mn(salen)]+. Each manganese complex connects two clusters through Nb−CN−Mn−NC−Nb bridges, leading to the formation of anionic layers interleaved by (Me4N)+. In 3, every cluster unit [Nb6Cl12(CN)6]4- is linked to two [Mn(salen)(MeOH)]+ units through two apical trans cyanide ligands, leading to the formation of trimeric units {Mn−(NC)[Nb6Cl12(CN)4](CN)−Mn}. Every trimeric unit connects to two neighboring units through hydrogen bonding between OMeOH from coordinated methanol ligand and NCN from two neighboring clusters, resulting in the formation of anionic chains along the crystallographic a axis {[Mn(salen)(MeOH)]2[(Nb6Cl12)(CN)6]}2-. The chains are separated by (Et4N)+ and MeOH. Magnetic properties and thermal behavior of these new hybrid inorganic−organic compounds are presented

Unexpected Reactivity of the 9-Aminoacridine Chromophore in Guanidylation Reactions

The 9-aminoacridine chromophore is an important building block of DNA-targeted chemotherapeutic agents. The success of 1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea as a carrier group in cytotoxic platinum−intercalator conjugates prompted us to explore the synthesis of an analogous guanidine-functionalized acridine. In a successful effort to generate such a derivative, various methods of guanidylation were employed, which demonstrate that the acridine C9−N9 linkage is highly susceptible to electrophilic and nucleophilic attack. The newly established reactivities provide efficient pathways to novel cyclic and spirocyclic acridine derivatives

Assembly of Hybrid Inorganic−Organic Materials from Octahedral Nb₆ Clusters and Metal Complexes

The octahedral edge-bridged niobium cyano-chloride cluster [Nb6Cl12(CN)6]4- and the [Mn(salen)]+ metal complex have been used as building units to prepare solid-state materials with extended frameworks at room temperature through self-assembly processes. Three materials with different dimensionalities were prepared and characterized:  (Me4N)4[Nb6Cl12(CN)6]·2MeOH (1) (0D), (Me4N)2[Mn(salen)]2[Nb6Cl12(CN)6] (2) (2D), and (Et4N)2[Mn(salen)(MeOH)]2[Nb6Cl12(CN)6]·2MeOH (3) (1D). 1 was used as cluster precursor for the preparation of 2 and 3. The framework dimensionality seems to be affected by the size of the template-counterion used. Single-crystal X-ray analysis revealed that 1 is based on discrete [Nb6Cl12(CN)6]4- separated by (Me4N)+ and MeOH molecules. 2 has a two-dimensional framework, in which each layer is formed by [Nb6Cl12(CN)6]4- clusters connected through four cyanide ligands to four different [Mn(salen)]+. Each manganese complex connects two clusters through Nb−CN−Mn−NC−Nb bridges, leading to the formation of anionic layers interleaved by (Me4N)+. In 3, every cluster unit [Nb6Cl12(CN)6]4- is linked to two [Mn(salen)(MeOH)]+ units through two apical trans cyanide ligands, leading to the formation of trimeric units {Mn−(NC)[Nb6Cl12(CN)4](CN)−Mn}. Every trimeric unit connects to two neighboring units through hydrogen bonding between OMeOH from coordinated methanol ligand and NCN from two neighboring clusters, resulting in the formation of anionic chains along the crystallographic a axis {[Mn(salen)(MeOH)]2[(Nb6Cl12)(CN)6]}2-. The chains are separated by (Et4N)+ and MeOH. Magnetic properties and thermal behavior of these new hybrid inorganic−organic compounds are presented

A New Quasi-One-Dimensional Niobium Oxychloride Cluster Compound Cs₂Ti₄Nb₆Cl₁₈O₆: Structural Effects of Ligand Combination

The new niobium oxychloride cluster compound, Cs2Ti4Nb6Cl18O6, was obtained by solid-state synthesis techniques in the course of our systematic investigation of metal oxychloride systems aimed at the preparation of low-dimensional cluster compounds. Cs2Ti4Nb6Cl18O6 crystallizes in the trigonal system, with unit cell parameters a = 11.1903(7), c = 15.600(2) Å, space group P3̄1c, Z = 2. Its crystal structure was determined by single-crystal X-ray diffraction techniques. The full-matrix least-squares refinement against F2 converged to R1 = 0.048 (Fo > 4σ(Fo)), wR2 = 0.069 (all data). The structure is based on an octahedral cluster unit (Nb6C )C in which the six edge-bridging oxide ligands are arranged in two sets of three on opposite sides of the Nb6 octahedron. Ti3+ ions link the clusters through Oi and Cla ligands to form linear chains running along the c axis. The location of titanium ions correlates with the arrangement of oxide ligands around the Nb6 metal core. The chains interact with each other through additional Ti3+ and Cs+ ions. Interchain interactions are significantly weaker than intrachain interactions, resulting in a quasi-one-dimensional character of the overall structure

Diastereoselective and Intramolecular Cycloadditions of Asymmetric <i>P-</i>Nitroso Phosphine Oxides

Benzyl phenyl P-nitroso phosphine oxide (5) reacts as an N−O heterodienophile with 1,3-cyclopentadiene to give the diastereomeric cycloadducts 6a,b in a ratio of 1.5:1 (6a:6b). The same reaction in the presence of tin tetrachloride produces 6a,b in a ratio of 2.9:1 (6a:6b). Cycloaddition of the structurally modified P-nitroso phosphine oxide (18) with 1,3-cyclopentadiene forms the diastereomeric cycloadducts 16a,b in a ratio of 3.1:1 (16a:16b). These results suggest the reactions of these P-nitroso phosphine oxides and 1,3-cyclopentadiene occur through a transition state where the heterodienophile adopts an s-cis conformation and approaches the diene in an exo fashion syn to the phenyl group. This model resembles those proposed for the cycloadditions of the structurally similar asymmetric vinyl phosphine oxides. Reaction of 18 with 1,3-cyclopentadiene in the presence of a Lewis acid produces cycloadducts 16a,b in a ratio of 7:1 (16a:16b), which approaches synthetic utility. Similar experiments show that 1,3-cyclohexadiene likely reacts with P-nitroso phosphine oxides through a different transition state, limiting current predictions regarding the diastereoselectivity of these reactions. The intramolecular cycloaddition of an asymmetric P-nitroso phosphine oxide (19) for the first time produces a unique phosphorus-containing heterocyclic compound (20)

Unexpected Reactivity of the 9-Aminoacridine Chromophore in Guanidylation Reactions

The 9-aminoacridine chromophore is an important building block of DNA-targeted chemotherapeutic agents. The success of 1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea as a carrier group in cytotoxic platinum−intercalator conjugates prompted us to explore the synthesis of an analogous guanidine-functionalized acridine. In a successful effort to generate such a derivative, various methods of guanidylation were employed, which demonstrate that the acridine C9−N9 linkage is highly susceptible to electrophilic and nucleophilic attack. The newly established reactivities provide efficient pathways to novel cyclic and spirocyclic acridine derivatives

Duplex-Promoted Platination of Adenine-N3 in the Minor Groove of DNA: Challenging a Longstanding Bioinorganic Paradigm

The interactions of [Pt(en)Cl(ACRAMTU-S)](NO3)2 (PT-ACRAMTU, en = ethane-1,2-diamine, ACRAMTU = 1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea) with adenine in DNA have been studied using a combination of analytical and high-resolution structural methods. For the first time, a cytotoxic platinum(II) complex has been demonstrated to form adducts in the minor groove of DNA through platination of the adenine-N3 endocyclic nitrogen. An acidic depurination assay was developed that allowed the controlled and selective (pH 2, 60 °C, 12 h) release of platinum-modified adenine from drug-treated nucleic acid samples. From the digested mixtures, three adducts were isolated by semipreparative reverse phase high-performance liquid chromatography and studied by electrospray ionization mass spectrometry (in-line LC−MS), variable-pH 1H NMR spectroscopy, and, where applicable, X-ray crystallography. The three species were identified as the N7 (A*-I), N3 (A*-II), and N1 (A*-III) linkage isomers of [Pt(en)(ACRAMTU-S)(adenine)]3+ (A*). Incubations carried out with the single- and double-stranded model sequences, d(TA)5 and d(TA)15, as well as native DNA indicate that the adduct profiles (A*-I:A*-II:A*-III ratios) are sensitive to the nature of the nucleic acid template. A*-II was found to be a double-strand specific adduct. The crystal structure of this adduct has been determined, providing ultimate evidence for the N3 connectivity of platinum. A*-II crystallizes in the triclinic space group P1̄ in the form of centrosymmetric dimers, {[Pt(en)(ACRAMTU-S)(adenine-N3)]2}6+. The cations are stabilized by a combination of adenine−adenine base pairing (N6···N1 2.945(5) Å) and mutual acridine−adenine base stacking. Tandem mass spectra and 1H chemical shift anomalies indicate that this type of self-association is not merely a crystal packing effect but persists in solution. The monofunctional platination of adenine at its N7, N3, and N1 positions in a significant fraction of adducts breaks a longstanding paradigm in platinum−DNA chemistry, the requirement for nucleophilic attack of guanine-N7 as the principal step in cross-link formation. The biological consequences and potential therapeutic applications of the unique base and groove recognition of PT-ACRAMTU are discussed

The First Coordination Polymers and Hydrogen Bonded Networks Containing Octahedral Nb₆ Clusters and Alkaline Earth Metal Complexes

Three novel coordination polymers built of octahedral niobium cyanochloride clusters [Nb6Cl12(CN)6] and alkaline earth metal complexes have been prepared by reaction of aqueous solutions of (Me4N)4Nb6Cl18 and KCN with solutions of alkaline earth metal salts and 1,10-phenanthroline (phen) (1:2 molar ratio) in H2O/EtOH. The structures of [Ca(phen)2(H2O)3]2[Nb6Cl12(CN)6]·(phen)(EtOH)1.6 (1), [Ca(phen)2(H2O)2]2[Nb6Cl12(CN)6]·(phen)2·4H2O (2), and [Ba(phen)2(H2O)]2[Nb6Cl12(CN)6] (3) were determined by single-crystal X-ray diffraction. The three compounds were found to crystallize in the monoclinic system (space group Pn) with a = 11.5499(6) Å, b = 17.5305(8) Å, c = 21.784(1) Å, β = 100.877(1)° for 1; triclinic system (P1̄) with a = 12.609(4) Å, b = 13.262(4) Å, c = 16.645(5) Å, α = 69.933(6)°, β = 68.607(6)°, γ = 63.522(5)° for 2; and a = 16.057(1) Å, b = 16.063(1) Å, c = 16.061(1) Å, α = 86.830(1)°, β = 64.380(1)°, γ = 67.803(1)° for 3. Compounds 1 and 2 are built of cluster anions [Nb6Cl12(CN)6]4- trans-coordinated by two Ca2+ complexes via CN ligands to form neutral macromolecular units [Ca(phen)2(H2O)3]2[Nb6Cl12(CN)6] in 1 and [Ca(phen)2(H2O)2]2[Nb6Cl12(CN)6] in 2. Water of coordination and cyanide ligands form hydrogen bonded 3D and 2D frameworks for 1 and 2, respectively. The structure of 3 consists of [Nb6Cl12(CN)6]4- cluster anions and [Ba(phen)2(H2O)]2+ complexes linked through bridging cyanide ligands to form a neutral three-dimensional framework in which each barium complex is bound to three neighboring Nb6 clusters and each Nb6 cluster is linked to six Ba complexes