Synthesis And Biological Activities Of Novel Ferrocene-containing 13-cis-retinoic Acid And Penem Derivatives

The discovery of ferrocene and elucidation of its remarkable structure is arguably the starting point for modern organometallic chemistry. Recently, increasing interests have been focused on developing structural variations of established drugs by metallocenic organometallic compounds as alternatives of the chemotherapy of drug-resistance in cancer and tropical diseases. The stability, non-toxicity and readily membrane-permeation of the ferrocenyl group, the accessibility of a large variety of derivatives, as well as its favourable electrochemical properties have made ferrocene and its derivatives very suitable for biological applications and for conjugation with biomolecules. Accordingly, using ferrocenyl-containing derivatives as medicines and other chemotherapeutants has long been recognized as an attractive way. The research work of this dissertation is summarized as follows:(I) 13-cis-retinoic acid and other retinoids are currently used for treatment of dermatological disorders and as chemotherapeutic agent against various endothelial cancers, breast cancer, and endometrial cancer. However, retinoids, including retinoic acids, have been found to be too toxic at high dosage levels to be of practical value for cancer prevention in higher mammals. Side effects such as teratogenicity, hepatotoxicity, and headaches have been observed as a result when the most of these compounds were used. Researchers have been pursuing the discovery and synthesis of novel retinoic acid analog in order to increase their therapeutic efficiency and/or reduced toxicity.In order to decrease toxicities of retinoids, enhance physiological Activities against cancer cells and increase absorbency in the organisms, eight novel 13-cis-Retinoyl ferrocene derivatives (25—32) were synthesized through Mitsunobu reaction and their structures were characterized Mitsunobu reaction have many advantages on the synthesis of such compounds as following: (1) The environment of reaction is mild, It inherits the advantage of DCC/DMAP method, the structure of 13-cis-Retinoyl was not changed. (2) The reaction time is 20-22h shorter than DCC/DMAP method. (3) The yield of production is higher than 70%. Compared to DCC/DMAP method, it is 30% higher. (4) Resolved the problem that the products and by-products were difficult to separate becasuse their polarity is similar in the DCC/DMAP method.The cytotoxic activities of the new retinoyl derivatives (25—32) were determined in vitro by MTT assay using human cancer lines including A549 cells、BEL7407 cells and Tca cells lines. Results showed that all the compounds have cytotoxic activities and the 13-cis-Retinoyl ferrocene derivatives exhibited more excellent cytotoxic activities against cancer cells than parent 13-cis-retinoic acid.(II) In order to prepare some arylsubstituted ferrocenes to evaluate their structure-activity relationships, herein we report on the scope of the palladium- catalyzed ferroceneboronic acid coupling reaction with organic triflates and their synthetic application. We found the coupling reaction could not proceed completely under standard Suzuki coupling conditions. But it proved successful under reflux condition with shorter reaction time and high yield. The results indicated that aryl triflates having electron-withdrawing group gave better yields than those having electron-donating group. Because aryl triflates could be prepared from corresponding phenol or aniline, we proposed a new method which could be used for synthesis of arylsubstituted ferrocenes starting from substituted phenol or aniline.The successful conversion of aryl triflates into arylsubstituted ferrocenes prompted us to extend the reaction to vinyl triflates. Fortunately the above reaction conditions were proved to be satisfactory when applied to them. Vinyl triflates could be prepared in high yield from regiospecifically generated enolates by trapping with N-phenyltrifluoromethanesulfonimide, so we proposed a new method which could be used for synthesis of vinyl-substituted ferrocenes starting from ketones; moreover, this reaction was regiospecific.(III) A highly efficient and convenient synthesis of the very useful penem precursor 4-acetoxyazetidinone (4-AA) was described in about 30% overall yield. (1) 6, 6-Dibromopenicillanate-1β-sulfoxide (67) was employed as a key intermediate and involved in the crucial acetaldehyde condensation with complete stereoselectivity. (2) A greatly improved Zn-NH4OAc-THF reduction method was developed in this process and afforded almost exclusively trans product (69) in 80% yield. (3) Treatment of the penicillin sulfoxide (70) with 2-mercaptobenzothiazole followed by base-catalyzed double-bond isomerization afforded a conjugated ester disulfide (71) in almost quantitative yield. This method could keep the original configuration. (4) Reductive alkylation of the disulfide 71 by NaBH4 in DMF with subsequent addition of CH3I afforded the 4-methyl thioazetidinone (72) in one step in 85% yield. (5) A convenient procedure for the removal of N-substituent from the azetidinone 72 was developed in treatment with potassium permanganate in phosphate buffer at ice-bath temperature. (6) N-bromosuccinimide was used to overcome the drawbacks of the heavy metal reactant to convert of the methylthio group to acetoxy in good yield.Its ease of workup, good overall yield, excellent stereoselectivity and mild reaction conditions made this process a very practical alternative to the existing methods.(IV) Penems were syntheticβ-1actam antibiotics that, as a class, possessed a number of interesting properties which included a broad antibacterial spectrum and low susceptibility to hydrolysis byβ-lactamases but, at the same time, were inactivated by renal dipeptidases found in the brush border of the kidney. Many penems possessed a side-chain at C2 that incorporates an aromatic or heteroaromatic group, for example, faropenem were in current clinical use. A series of new penems (84a—84h) were synthesized by structural modifications with ferrocenyl groups at the C2 position of the penem nucleus in order to enhance its antimicrobial activities and understand structure-activity relationships in these penem derivatives. A highly effective method was developed in the oxalimide cyclization forming penems at lower temperature and higher yields compared to the conventional methods. A very practical deprotection procedure of TBS ether and allyl ester of the penems by use of inexpensive ammonium bifluoride and palladium acetate respectively was also described. To our knowledge these represented the best methods achieved so far for synthesizing this series of antibiotics.Their in vitro antibacterial activities against both Gram-positive including MRSA and Gram-negative bacteria were tested. Most of the penems exhibited superior or equivalent efficacy of antibacterial activity compared with faropenem. In particular, compound 84h having a heterocyclic group showed the most potent antibacterial activity.