Design, Synthesis And Bioactivity Study Of Acridine Derivatives Containing Boronic Acid

Boronic acids were used in the field of life sciences recently. The boron atom of boronic acids is sp2 hybridized and electron-deficient, hence it can bind with the hydroxide of Thr and Ser residues or the N atom of imidazole ring of His, meanwhile the two hydroxide redicals can interact with the amino or carbonyl group by forming hydrogen bonds. Namely, boronic acids can actively interact with electron-rich systems. Organic boronic acids, which can form five/six membered cyclic lactones by coupling with cis-1,2-or cis-1,3-diols, were widely used as molecular receptors of monosaccharides and also applied to selective binding of tumor cell-surface carbohydrates. The key point distinguished malignant tumor cells from normal ones is the change of cell-surface N-carbonhydrates, which is characterized by the increase of fucose and sialic acid at the end of carbohydrate chains; thus, many distinctive carbonhydrate chains become cancer molecular markers. However, reports employing modification of carbohydrate chains to increase the selectivity of corresponding cancer medicine are yet unknown.sLex could be recognized by boronic acids while sLex antigens are highly expressed on white blood cells and the number of sLex antigen also notably increase on acute myeloid leukemia cells. Acute myeloid leukemia is clinically treated by amsacrine, whose acridine-ring can plug into DNA base pairs assisted by its side chains. Accordingly we designed acridine derivatives containing boronic acid. Boronic acid can recognize particular sugar and then enrichment drug in the tumor tissue. When acridine plug into DNA base pairs, boronic acid can interplay with DNA skelecton participate of negative charge, hence it can raise curative effect.The details of this paper are as follows:1. There series of acridine derivatives containing boronic acid were designed and synthesized refer to amsacrine. Methodology was discussed in the chemical reactions of boronic acid.1) Substituent groups on benzene ring had crucial influences on the experiment results in coupling reactions of bis(pinacolato)diboron with aromatic halides under the catalyzation of PaCl2(dppf). Electron withdrawing groups can enhance the reactions, but electron donating groups can impede the reactions. The activity of C-I bond is greater than C-Br bond. We obtained free boronic acids by using NaI04 to cleavage pinanediol boronate esters. Electron donating groups can fasten the reactions, but electron withdrawing groups can decrease the reaction rates. The importance of time to the reactions was discussed. Two resins containg phenylboronic acid were prepared by coupling reactions of aminomethyl polystyrene resin with p-carboxyl phenylboronic acid or 3-carboxyl-5-nitro-phenylboronic acid. Pinanediol boronate esters were cleavaged by transesterification.2) When carboxylphenylboronic acid reacted with amine, Boronobenzamide derivatives were conveniently preparated in high yield using DMT-MM instead of normal coupling reagents in alcohol.3) It is very difficault to purify the compounds containing boronic acid. Boronic acid is a specially group. Aryl boronic acid can form boroxine, which is the cyclotrimetric anhydride of boronic acid with different equilibrium constants. Boronic acid is not stable under strong alkaline or acidic conditions.Phenylboronic acid can be converted into phenol by silicon gel. N,N-Diethanolaminomethyl polystyrene (DEAM Resin) can purify boronic acid facialy. We simplify the preparation of DEAM Resin according to the reaction between Merrifield Resin and triethylamine. We obtained the target products using Merrifield Resin successfully. To deprotect pinacolyl boronate esters using DEAM Resin was found. The bromomethyl phenylboronic acid can be fixed on DEAM Resin, then reacted with aniline. The obtained N-benzylaniline reacted with iodomethane. Afer hydrogenolysis N-methylaniline was obtained. This is one method to prpare secondary amine.2. Antitumor activity was studied in two cell models lung cancer cell line H1650 which stably express survivin reporter or cisplatin-resistant reporter genes. The tests show that several compounds have evident activity at 1μM. Compound B16 shows the highest activity toward lung cancer cell expressing survivin reporter genes. Compound B54 shows the highest activity toward lung cancer cell expressing cisplatin-resistant reporter genes...