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2 2007

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Leki przeciw grypie. Synteza tamiflu® - leku gromadzonego, aby zapobiec epidemii ptasiej grypy

Karchier M., Michalak K., Wicha J.

Wiadomości Chemiczne

2007

[Z] 61, 1-2

7-42

Influenza (flu) and related viral infections present a constant threat to public health. World-wide efforts have been recently initiated (coordinated by WHO) to prevent global epidemic in view of spreading deadly bird flu virus (H5N1) among people. Attention has been focused on Tamiflu® (1, Figure 1), synthetic, orally active drug manufactured by Hoffmann - La Roche On the surface of the flu virus there are located two proteins important for infecting animal cell: hemagglutinin and neuraminidase (sialidase). Hemagglutinin is responsible for the recognition of specific sialic acids in the cell membrane glycoconjugates; neuraminidase is involved in subsequent hydrolysis of sialic acid residue and is crucial for the virus propagation. Sialic acids are sugar-related keto-acids, as neuraminic acid 2. Their structure is specific for a given species. Functions of hemagglutinin or neuraminidase have been targeted in systematic search for anti-flu drugs. The first efficient neuraminidase competitive inhibitor Relanza® (Zanamivir) has been obtained as a mimic of hypothetic oxonium ion involved in sialic acid hydrolysis. Many structures related to Zanamivir have been investigated]. The most successful line of research has been aimed at synthesis of carbocyclic neuraminic acid derivatives from (-)-quinic or (-)-shikimic acids. The Gilead-Roche "first generation" analogue with the double bond oriented toward the hydroxy-group 33 proved more active than its counterpart 34. Further modification of the structure 33 was based on X-ray analysis of protein - inhibitor complexes and led to Tamiflu®. Prime synthesis of Tamiflu® from (-)-shikimic acid involved several steps. Since this starting material is rather expensive more economic approaches have been studied. The technological approach to the key epoxide 75 from (-)-quinic acid involves bicyclic lactone 70 controlled dehydration to form 73 and regiospecific acetal reduction using borane-dimethylsulfide complex in the presence of a silylating agent. Use of the developed methods and shikimic acid as the starting material allowed for an efficient access to the target epoxide 75. The epoxide 75 has been transformed into the final product in several steps. Most advanced synthetic routes transforming 75 into Tamiflu® rely upon the use of tert-butylamine and then diallylamine. Current studies on transformation of glucose into shikimic acid by genetically modified strain of Escherichia coli are likely to secure supplies of this convenient starting material for Tamiflu® production. E. J. Corey et al. have developed enantioselective total synthesis of Tamiflu®. [2+4] cycloaddition reaction of butadiene and trifluoroethylacrylate in the presence of a chiral oxazoborolidine catalyst provided cyclohex-3-enecarboxylic acid derivative (87, Scheme 19). Transformation of 87 into 99 embraced several steps, including the novel haloamidation (86 into 97). The synthesis route involved 12 steps and afforded Tamiflu® in 25% overall yield. Catalytic enantioselective reaction of the easily accessible meso-aziridine 101with trimethylsilylazide provided the cornerstone to total synthesis of Tamiflu® by M. Shibasaki et al. [48]. The synthetic route from azide 102 to the target involved several steps (Schemes 23 and 24). Among them the efficient allylic oxidation of 109 and the nickel-catalyzed conjugate addition of trimethylsilylcyanide to ?,?-unsaturated ketone 110 that contribute to general synthetic methodology. In the synthesis developed by Cong i Yao [51], the starting material - serine-derived aldehyde 117 (Garner's aldehyde, Scheme 25) has been selected from the "chiral pool". The synthesis involves a sequence of diastereoselective reactions and the ring-closure metathesis reaction (130 into 131) using the II generation Grubbs catalyst. Approaches to Tamiflu® illustrate the impressive achievements of organic synthesis. However, at present the high cost of this drug may hamper its broader application.

Kompleksy platyny (IV) jako potencjalne związki przeciwnowotworowe

Ciołkowski M., Budzisz E.

Wiadomości Chemiczne

2007

[Z] 61, 1-2

43-60

Cisplatin is an important anticancer drug. Unfortunately it does not bring satisfactory effects in all types of tumor. Other problems are its toxicity and intrinsic or acquired resistance of tumor cells. That is why new drugs based on this molecule are being searched. One of the promising group of chemical compounds are neutral platinum(IV) complexes. They are more inert than platinum(II) complexes. In consequence their reactivity in bloodstream is weaker and more molecules can reach their target. Many studies were done to establish the relation among the structure, lipophilicity, reduction potential and cytotoxicity of those complexes. It is believed that platinum(IV) complexes must be reduced to platinum(II) complexes to obtain cytotoxicity. The speed of reduction depends on the nature of axial ligands. The complexes with chloride ligands are reduced the most quickly and complexes with hydroxide ligands are reduced the most slowly. In vitro cytotoxic activity of those complexes was shown to depend on their reduction potential. However suggestions exist that this result can be misleading for their in vivo activity, as platinum(IV) complexes are pro-drugs and might be inactive before reaching cancer cells. In a study of group of platinum(IV) complexes, derivatives of cisplatin and dichloroethylenediamineplatinum(II), a tendency for an increase of cytotoxic activity when lipophilicity increased was observed. However in a study of tetrakis(carboxylato)(1,2-diaminocyclohexane)platinum(IV) complexes, different cytotoxic activity of complexes possessing similar lipophilicity was observed. Hence lipophilicity of complex is important but it is not the only factor that determines complex activity. In other studies complexes of general structure cis, trans, cis-[PtNH3(RNH2)Cl2(OCOR')2] were examined. The research showed an increased activity of compounds with longer carbon chains of carboxylate axial ligands. It was also revealed that complexes with alicyclic amine ligands were more cytotoxic than those with aliphatic or aromatic amine ligands. Hall et al. revealed that platinum(IV) complexes, derivatives of cisplatin and dichloroethylenediamineplatinum(II), are active against DLD-1 colon cancer cell line in hypoxic environment. An examination of trans-dichlorodihydroxo(dimethylamine)(isopropylamine)platinum(IV) revealed its greater cytotoxic activity against A2780, CH1 and 41M human ovarian cancer cell lines, in vitro. Moreover this complex was shown to be active against A2780cisR, CH1cisR and 41McisR human ovarian cell lines which are resistant to cisplatin. Two platinum(IV) complexes: iproplatin (cis, trans, cis-dichlorodihydroxobis(isopropylamine)platinum(IV)) and tetraplatin (tetrachloro(cyclohexane-1,2-diamine)platinum(IV)) have had entered clinical trials. However iproplatin occurred to be less active than cisplatin and tetraplatin turned out to be neurotoxic. Presently two other complexes seem to be very promising: satraplatin (bis(acetato)amminedichlorocyclohexylamineplatinum(IV)) and adamplatin (bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV)). Both have entered clinical trials. There are some "nonstandard" approaches to investigating platinum complexes. For example platinum(IV) complexes with radioactive iodine isotope or with enzyme inhibitor were examined. Studies mentioned above present different approaches to searching for anticancer drugs among platinum(IV) complexes. Despite all encountered difficulties during researching platinum(IV) complexes, this group of compounds still seems to be potential source of new anticancer drugs.