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

• Autorzy: Karchier M. , Michalak K. , Wicha J.

Warianty tytułu

EN

Anti-virus drugs. synthesis of tamiflu® - a drug chosen to prevent the avian flu epidemic

• Języki publikacji: PL

Abstrakty

EN

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.

Słowa kluczowe

PL

metoda syntezy; synteza enancjoselektywna; kwas chinowy; kwas szikimowy; czynnik przeciwwirusowy; zależność struktura-aktywność

EN

synthetic method; enantioselective synthesis; quinic acid; shikimic acid; antiviral agents; structure-activity relationship

• Wydawca: Polskie Towarzystwo Chemiczne
• Czasopismo: Wiadomości Chemiczne
• Rocznik: 2007
• Tom: [Z] 61, 1-2
• Strony: 7--42
• Opis fizyczny: bibliogr. 54 poz., wykr.

Twórcy

autor

Karchier M.

autor

Michalak K.

autor

Wicha J.

• Instytut Chemii Organicznej Polskiej Akademii Nauk, ul. Kasprzaka 44/56, 01-224 Warszawa

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