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De enzymen protein:farnesyl transferase (PFT) en protein:geranylgeranyl transferase-1 (PGGT-1) zijn verantwoordelijk voor de post-translationele modificatie van kleine G-eiwitten noodzakelijk voor hun binding aan celmembranen. Sinds het begin van de jaren __80 is bekend dat het remmen van PFT voorkomt dat bepaalde gemuteerde G-eiwitten die kanker veroorzaken volwassen worden. Naast anti-kanker therapie_n, zijn er de laatste jaren steeds meer duidelijke aanwijzingen dat PFT en PGGT-1 remmers voor andere therapeutische toepassingen gebruikt kunnen. Hierbij gaat het om bestrijding van osteoporose (botontkalking), atherosclerose en restenose (aderverkalking), angiogenese (de vorming van nieuwe bloedvaten), malaria en multiple sclerose. Mogelijk zal dit jaar de PFT remmer Tipifarnib__ (Johnson & Johnson) goedgekeurd worden voor de behandeling van Acute Myelo_de Leukemie. Het proefschrift beschrijft enkele synthetische methoden voor het ontwikkelen van potente PFT en PGGT-1 remmers (in samenwerking met Gaubius Laboratorium, TNO Quality of Life). Zo is voor PFT een potente en selectieve PFT remmer ontwikkeld waarvan de werking in cellen ook is aangetoond. Naast de bio-organische synthetische methoden, is een __proteomics__ (onderzoek naar eiwitten en hun functie in de cel) methode ontwikkeld dat het mogelijk moet maken om tot nu toe onbekende PFT en PGGT-1 substraten te isoleren en identificeren.|The prenyl transferases protein:farnesyl transferase (PFT) and protein:geranylgeranyl transferase-1 (PGGT-1) are responsible for the post-translational modification of small Gproteins. This post-translational modification comprises the attachment of an isoprenoid (farnesyl or gerangeranyl) to the C-terminus of the G-protein and is essential for a proper cellular membrane localization and function. Since the beginning of the 80__s it is known that inhibition of PFT prevents the maturation of certain mutated (small) G-proteins involved in tumorogenesis. Besides anti-cancer therapies, it is becoming more and more obvious that PFT and/or PGGT-1 inhibitors also hold promise for the treatment of osteoporosis (bone resorption), atherosclerosis and restenosis (thickening of the inner lining of an artery), angiogenesis (formation of new bloodvessels), malaria and multiple sclerosis. At the moment the PFT inhibitor Tipifarnib_ (Johnson & Johnson) has been submitted for approval by the FDA for the treatment of Acute Myeloid Leukemia (AML). The Thesis by Farid El Oualid presents several synthethic approaches toward the development of potent PFT and/or PGGT-1 inhibitors (in cooperation with the Gaubius Laboratory, TNO Quality of Life). For PFT a potent and very selective inhibitor was found. Besides being active against pure PFT, the inhibitor was also shown to be active in cultured cells. In addition to the bio-organic synthethic methods, a __proteomics__ strategy was developed which should make it possible to isolate and identify unknown PFT (and PGGT-1) substrates

The synthesis of a novel hapten containing a 1,4-diamino-2,3-diolbutane core unit is described. The molecule contains four stereogenic centres and has been synthesised via a stereoselective route. The absolute stereochemistry of each stereogenic carbon atom has been assigned by nuclear Overhauser effect experiments carried out on a number of derivatives. (C) 2004 Elsevier Ltd. All rights reserved.

Three diastereoisomeric hydroxyethylene isosters of the Val- Ala dipeptide were synthesized from α,β-unsaturated ketones 1 derived from N-Boc- and N,N-dibenzyl-L-valine. The enones were hydrocyanated with diethylaluminum cyanide to give the corresponding β-cyano ketones with the stereoselectivity depending on the protecting group. N-Boc protected enone 1a gave a 1:1 mixture of anti and syn adducts 4a, 5a while the corresponding N,N-dibenzyl compound 1c gave a 6:1 mixture of anti, syn adducts 4c, 5c. Borohydride reduction of the resulting cyano ketones is also controlled by the protecting group, resulting in opposite stereoselectivities for N-Boc and N,N-dibenzyl compounds. The cyano alcoholsthus obtained were converted, in several steps, into two series of enantiomerically pure hydroxyethylene isosters of the Val-Ala dipeptide. In the first series the hydroxy group and the N-terminal of the isoster are internally protected through the formation of an oxazolidine; in the second series the hydroxy group and the C-terminal are protected as lactone. Two oxazolidines (28, 29), corresponding to syn,syn and syn,anti 4-hydroxy-5-amino acid isosters, and three lactones (23−25), corresponding to syn,syn, syn,anti, and anti,anti isosters were obtained by this approach.

A highly efficient route is presented for the synthesis of N-protected isosteric dipeptides Pheψ[COCH 2 ]Gly and Pheψ[CH(OH)CH 2 ]Phe from L -phenylalanine through 2-thiazolyl α-amino ketone and δ-amino-γ-hydroxy-(E)-α,β-enoate derivatives as key intermediates.