Aminoalkoxyfluorenones and aminoalkoxybiphenyls: DNA binding modes.

Many evidences suggest that DNA-drug interaction in the minor groove and the intercalation of drugs into DNA may play critical roles in antiviral, antimicrobial, and antitumor activities. As a continuous effort to develop novel antiviral agents, the series of planar fluorenone (3a-7d) were synthesized and used along with nonplanar biphenyls (11a-d) for the comparative analysis of their interaction with DNA. The chemical structure of new compounds was confirmed by 1H NMR, 13C NMR and mass spectra as well as elemental analysis. DNA affinity of 3a-7d and 11a-d was evaluated by ethidium bromide displacement assay. Affinity constant (lgKa) of 3a-7d was found to be approximately two orders of magnitude higher than constants of corresponding 11a-d. The molecular docking of aminoalkoxybiphenyls (11a-d) into minor grove of five different nucleotide sequences (d(CCIICICCII), d(CGCGTTAACGCG), d(CGCGATATCGCG), d(GGCCAATTGG), d(GGATATATCC)) demonstrated their binding capacity to the specific DNA site. The linear least squares fitting technique was successfully applied to derive an equation describing the relationship between lgKa and SF.

Benzylic Functionalisation of Phenyl all-cis-2,3,5,6-Tetrafluorocyclohexane Provides Access to New Organofluorine Building Blocks.

Selectively fluorinated hydrocarbons continue to attract attention for tuning pharmacokinetic properties in agrochemical and pharmaceutical discovery programmes. This study identifies benzylic bromination of phenyl all-cis-2,3,5,6-tetrafluorocyclohexane 2 as a key reaction for accessing building blocks containing the all-cis-2,3,5,6-tetrafluorocyclohexane ring system. These cyclohexanes are of interest as the fluorines are only on one face of the cyclohexane, and this imparts an unusual polar aspect, very different to an otherwise hydrophobic cyclohexane. Ritter type reactions of benzyl bromide 4 with DMF and acetonitrile generated the corresponding benzyl alcohol 6 and benzylacetamide 7 respectively. Benzylacetamide 7 was hydrolysed to benzyl amine 8 and syn-amino-alcohol 9, and separately the phenyl ring was oxidatively cleaved to furnish carboxylic acid acetamide 10, which after hydrolysis gave the tetrafluorocyclohexyl amino acid 11. A trans-halogenation of benzylbromide 4 with AgF2 gave benzyl fluoride 13. Oxidative cleavage of the aryl ring then gave pentafluorocyclohexyl carboxylic acid 14. This carboxylic acid was readily converted to amides 23-26 and the preferred conformations of these α-fluoroamides were explored by DFT, X-ray structure and 1 H-19 F HOESY NMR analysis.

Fluorinated cyclohexanes: Synthesis of amine building blocks of the all-cis 2,3,5,6-tetrafluorocyclohexylamine motif.

This paper reports the synthesis of three amine stereoisomers 5a-c of the tetrafluorocyclohexyl ring system, as building blocks for discovery chemistry programmes. The synthesis starts from a Birch reduction of benzonitrile, followed by an in situ methyl iodide quench. The resultant 2,5-cyclohexadiene was progressed via double epoxidations and then hydrofluorination ring opening reactions. The resultant fluorohydrin moieties were then converted to different stereoisomers of the tetrafluorocyclohexyl ring system, and then reductive hydrogenation of the nitrile delivered three amine stereoisomers. It proved necessary to place a methyl group on the cyclohexane ring in order to stabilise the compound against subsequent HF elimination. The two all-cis tetrafluorocyclohexyl isomers 5a and 5b constitute facially polarized cyclohexane rings, with fluorines on the electronegative face and hydrogens on the electropositive face.

Multicomponent reactions of methyl substituted all-cis tetrafluorocyclohexane aldehydes.

This paper reports the preparation of methyl substituted all-cis tetrafluorocyclohexanes prepared from a Birch reduction of benzoic acid, worked up with a methyl iodide quench. The resultant methylcyclohexadiene carboxylic acid was reduced to the alcohol, protected as an ether and then a sequence of functional group manipulations carried out to introduce four fluorines. The cyclohexadienyl ring was then epoxidised and the C-O bonds sequentially converted through deoxyfluorination reactions to two sets of isomers of all-cis tetrafluorocyclohexane isomers. The blocking methyl group renders the ring safe to hydrogen fluoride elimination. Deprotection of the benzylic ether and then oxidation gave aldehydes which were then used in Ugi and Passerini multicomponent reactions, allowing this facially polarised cyclohexane to be incorporated into peptidic structural motifs.