Medicinal Chemistry and Pharmaceutical Technology Synthesis of integrin inhibitors
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1 Scientifica Acta 1, o. 1, (2007) Medicinal Chemistry and armaceutical Technology Synthesis of integrin inhibitors Massimo Serra Dipartimento di Chimica Farmaceutica, Università di Pavia, viale Taramelli 12, Pavia, Italy A series of azabicycloalkane amino acids, which can be regarded as conformationally restricted substitutes for e-pro dipeptide units have been synthesized. These bicyclic scaffolds are used as intermediates in the synthesis of biologically active cyclic peptidomimetic compounds comprising the sequence RGD (Arg- Gly-Asp). The most active cyclopentapeptide of the series was 1-RGD, which shows biological activity as selective α vβ 3 and α vβ 5 integrin inhibitor. The high affinity of 1-RGD towards α vβ 3 and α vβ 5 receptors, involved in tumor angiogenesis, led us to functionalize the azabicycloalkane scaffold with a suitable linker to which bioactive compounds could be appended; thus it would be possible to perform selective delivery of therapeutics and imaging agents to the tumor vasculature. ur work was focused on the synthesis of lactams 2a, 2b or 3, endowed with a vinyl moiety on a 7,5-fused 1-aza-2-oxo-bicycloalkane. Two different approaches exploiting as a key step either a Ring Closing Enyne Metahesis (RCEYM) or an intramolecular Sakurai reaction, have been studied. 1 Integrins and tumor angiogenesis Integrins are a family of heterodimeric transmembrane cell surface proteins, that are involved in cellcell and cell-matrix adhesion processes [1]. Currently, several integrin receptors have been identified, consisting of various combinations of at least 18 α and 8 β subunits, which assemble into 25 different receptors [2, 3]. Many of the receptors from the integrin family recognize the same amino acid core sequence Arg-Gly-Asp (RGD) [4], contained in a large number of matrix proteins (fibronectin, fibrinogen, vitronectin, osteopontin, etc.). Among such RGD-dependent integrins, the vibronectin receptors α v β 3 and α v β 5 have recently received increasing attention as interesting therapeutic targets, because of their critical role in tumor-induced angiogenesis and metastasis formation [5]. Integrins α v β 3 and α v β 5 are not generally expressed on epithelial cells and normal endothelial cells (EC), but they are significantly upregulated on activated EC and in metastatic tumor cells. Many integrins can be inhibited by small peptides that possess the Arg-Gly-Asp sequence as a common receptor recognition motif. Inhibition of α v β 3 integrins activity by cyclic RGD peptides and peptidomimetics has been shown to induce endothelial apoptosis [6] and inhibit angiogenesis [7, 8]. It is noteworthy that α v β 3 antagonists have very little effect on pre-existing blood vessels, indicating the usefulness of targeting this receptor for therapeutic benefit without side effects. Cyclic RGD pentapeptides have first been developed by Kessler s group as highly active and selective ligands for the α v β 3 integrin receptor [9 11]. An efficient procedure of spatial screening, based on the synthesis of stereoisomeric cyclic peptide libraries, led to the highly active α v β 3 -selective first generation cyclic pentapeptide cyclo(arg-gly-asp-d-e-val) [12 14]. The systematic derivatization of the lead peptide resulted in the -alkylated cyclopeptide cyclo(arg-gly-asp-d-e-[me]val) [15], which has entered clinical phase II studies as anticancer drug (Cilengitide, EMD121974). Recently, RGD peptides have been used as carriers for cytotoxic drugs, to specifically target cancer cells and tumor blood vessels. Furthermore, suitably radiolabeled RGD peptides have been developed for non invasive imaging of integrin expression during tumor angiogenesis, growth, and spread [16 18].
2 Scientifica Acta 1, o. 1 (2007) 97 Ring Closing Enyne Metathesis Intramolecular Sakurai reaction H 2 H () 3 H R H HCbz H H HCbz 2aR=H 2b R= 1-RGD 3 1 C 2 H Fig. 1: Scheme 1 The two different synthetic approaches devised to functionalize the azabicycloalkane scaffold 1. 2 Cyclic RGD pentapeptides containing azabicycloalkane scaffolds In the course of our studies we reported the synthesis of a series of azabicycloalkane amino acids, which can be regarded as conformationally restricted substitutes for e-pro dipeptide units [19 21]. Computational and spectroscopic studies have revealed that these bicyclic scaffolds can mimic reverseturn motifs [22]. The replacement of the D-e-[Me]Val dipeptide in the reference compound cyclo(rgdf[me]v) with such azabicycloalkane scaffolds leads to cyclopentapeptide 1-RGD [23] (scheme 1). This compound shows high affinity to α v β 3 integrin, inhibiting echistatin binding to α v β 3 with an IC 50 of 6.4 ± 0.1 nm (table 1). Interestingly, the affinity of 1-RGD for the α v β 3 integrin in this kind of assay was almost 30 and 3 times higher than the affinity of the lead structures c(rgdfv) and EMD121974, used as reference compounds. Future perspectives to employ 1-RGD as potential antitumor drug, led us to functionalize the azabicycloalkane scaffold 1 in a position located far from the RGD region. Thus, it would be possible to append covalently bound citotoxic molecules (doxorubicin, paclitaxel) or even contrast agents, useful in diagnostic imaging techniques. ur interest was focused on the synthesis of proline derived dipeptide mimetics having a 7,5-fused 1-aza-2-oxo-bicycloalkane structure functionalized with a vinyl group (2a, 2b or 3). In order to maximize the convergency of the synthetic plan, a single step leading to the contemporary formation of the lactam ring and the vinyl group would be desirable. Two different approaches exploiting as a key step either a Ring Closing Enyne Metahesis (RCEYM) [24] or an intramolecular Sakurai reaction [25], have been studied. Table 1: Inibition of the binding of [ 125 I]-echistatine on the α vβ 3and α vβ 5 receptors. The IC 50 was calculated as the concentration of compound required for 50% inhibition of ligand binding as estimated by the Allfit program. Values are means ± standard deviation of the determinations from three independent experiments. The well-characterized integrin antagonists cyclic pentapeptides c(rgdfv) and EMD were used as positive controls. Compound IC 50 [nm] for α v β 3 IC 50 [nm] for α v β 5 Echistatin 0.29 ± ± 0.02 c(rgdfv) 196 ± ± 0.03 EMD ± ± RGD 6.4 ± ± 0.04
3 98 Scientifica Acta 1, o. 1 (2007) RCEYM R H 5 R HCbz 2aR=H 2b R= HCbz 4aR=H 4b R= CH HCbz 6 Fig. 2: Scheme 2 Retrosynthetic analysis of vinyl lactams 2a and 2b. 3 Synthesis of lactams 2a and 2b via Ring Closing Enyne Metathesis Synthesis of vinyl lactams 2a and 2b could be performed exploiting a ring closing enyne metathesis of dipeptides 4a and 4b as shown by the retrosynthetic analysis reported in scheme 2. Most of the recent synthetic applications of RCEYM use ruthenium carbenes, such as Grubbs [26] and Hoveyda [27] catalysts, because of their availability, ease of use, functional group compatibility, and continued development. Following this synthetic approach, we obtained 4a submitting the propargyl prolyne 5 to condensation with -Cbz-(S)-vinyl phenylalanine 6, in presence of PyBRP as condensing agent. Propargyl proline 5 was easily prepared in two steps first treating the known -Boc-5-allyl proline methyl ester [21] with s 4 -ai 4, and then condensing the obtained aldehyde with the hira- Bestmann s reagent [28] (dimethyl 1- diazo-2-oxopropylphosphonate). In this way, we were able to prepare the corresponding enyne 4a with a good overall yield; substituted alkyne 4b was hence synthesized in excellent yield submitting 4a to a Sonogashira reaction with iodobenzene. Quaternary aminoacid 6 could be prepared in enantiomerically pure form, starting from L-serine, through a synthetic pathway recently developed in our laboratory. Attempts to prepare the targets diene 2a and 2b by RCEYM reaction of enynes 4a and 4b required a careful screening of various Ru precatalysts and reaction conditions. Unfortunately, vinyl lactams 2a and 2b could be obtained, in yields not higher than 10%, only through application of an ethylene atmosphere (Mori s conditions) [29] and by the use of a particular HC Ru precatalyst. Microwave heating was shown to dramatically reduce reaction times but not to improve yields (15% at best). After ascertaining that the RCEYM strategy was not a viable approach to unsaturated scaffolds 2a and 2b, an alternative synthetic plan was devised, involving an intramolecular Sakurai reaction. 4 Synthesis of lactam 3 via intramolecular Sakurai reaction This synthetic strategy is focused on the synthesis of vinyl lactam 3 exploiting as a key step an intramolecular Hosomi-Sakurai reaction of the aldehyde 7 (scheme 3). The synthesis of the hydroxymethyl dipeptide 8 was initially carried out in nine steps (scheme 4, path A) taking advantage of a coupling reaction between cis-5-allyl proline methyl ester [21] and (S) - Cbz--acetyl benzilserine 10, in presence of PyBRP as activating agents. The compound 10 could be achieved in enantiomerically pure form, starting from L-serine, through a modification of the synthetic protocol employed to obtain the (S)-vinyl phenylalanine. The final deprotection of the hydroxyl group provided the desired dipeptide 8 with an overall yield of 8%. Efforts to reduce the length of the synthetic scheme and raise the overall yield led us to explore a second approach involving the contemporary protection of the alcoholic and amino group of the quaternary amino acid 9 (path B).
4 Scientifica Acta 1, o. 1 (2007) 99 Si H H HCbz Intramolecular HCbz HCbz Sakurai Fig. 3: Scheme 3 Retrosynthetic analysis of vinyl lactam 3. L-serine 7steps CH H 2 2 H 9 3steps Ac C 2 H HCbz Cbz CH 2 C 2 H 5-allyl proline 5-allyl proline Ac Cbz HCbz CH 2 PathA overall yield: 8% H HCbz 8 PathB ov erall yield: 30% Fig. 4: Scheme 4 Synthesis of the hydroxymethyl dipeptide 8. The synthetic sequence started with the protection of the amino group in compound 9 as a Cbz derivative, followed by the conversion of the obtained (S) -Cbz-benzyl serine methyl ester into the corresponding,-aminal by treatment with 2,2-dimethoxypropane. Methyl ester saponification with LiH afforded the carboxylic acid intermediate 12, which was coupled with cis-5-allyl proline methyl ester in order to obtain the dipeptide 13. Subsequent hydrolysis of the oxazolidine ring by treatment with a mixture MeH/HCl 12 furnished the desired alcohol 8. The synthesis of the target compound 8 was thus accomplished with an overall 30% yield from benzyl serine methyl ester 9 (path B), significantly higher than the one provided by the previously reported method (path A). Moreover, the new protocol is characterized by a limited number of steps and can be easily applied to a multi-gram scale synthesis. The introduction of the allylsilane moiety was carried out submitting compound 8 to cross metathesis reaction [30] with allyltrimethylsilane in the presence of Grubbs II catalyst; best results were obtained performing this reaction in ethylene atmosphere. The following oxidation of the alcoholic function with PCC afforded the aldehyde 7, a suitable precursor for the successive intramolecular Sakurai reaction. Among the various Lewis acids tested, Sc(Tf) 3 was shown to be the best in terms of yield and mildness of the reaction conditions, affording the target homoallylic alcohol 3 in 60% yield, as a mixture of diastereoisomers. Experiments are underway to improve the hydrolysis yield of the intermediate 13 and to optimize the final intramolecular Sakurai allylation step. Acknowledgements MUR is acknowledged for funding (PRI2006 prot research program).
5 100 Scientifica Acta 1, o. 1 (2007) References [1] R. Hynes, Cell, 69, 11 (1992). [2] E. Ruoshlati, M. D. Pierschbacher, Science, 238, 491 (1987). [3] S. Kuphal, R. Bauer, A. K. Bosserhoff, Cancer and Metastasis Reviews, 24, 195 (2005). [4] S. L. Goodman, G. Holzemann, G. A. Sulyok, H. Kessler, Journal of Medicinal Chemistry, 45, 1045 (2002). [5] B. P. Eliceiri, D. A. Cheresh, Journal of Clinical Investigation, 103, 1227 (1999). [6] P. C. Brooks, A. M. Montgomery, M. Rosenfeld, R. A. Reisfeld, T. Hu, G. Klier, D. Cheresh, Cell, 79, 1157 (1994). [7] P. C. Brooks, S. Stromblad, R. Klemke, D. Visscher, F. H. Sarkar, D. A. Cheresh, Journal of Clinical Investigation, 96, 1815 (1995). [8] M. A. Buerkle, S. A. Pahernik, A. Sutter, A. Jonczyk, K. Messmer, M. Dellian, British Journal of Cancer, 86, 788 (2002). [9] M. Aumailley, M. Gurrath, G. Müller, J. Calvete, R. Timpl, H. Kessler, FEBS Letters, 291, 50 (1991). [10] M. Gurrath, G. Müller, H. Kessler, M. Aumailley, R. Timpl, European Journal of Biochemistry, 210, 911 (1992). [11] G. Müller, M. Gurrath, H. Kessler, R. Timpl, Angewandte Chemie International Edition, 31, 326 (1992). [12] R. Haubner, R. Gratias, B. Diefenbach, S. L. Goodman, A. Jonczyk, H. Kessler, Journal of the American Chemical Society, 118, 7461 (1996). [13] J. Wermuth, S. L. Goodman, A. Jonczyk, H. Kessler, Journal of the American Chemical Society, 119, 1328 (1997). [14] R. Haubner, D. Finsinger, H. Kessler, Angewandte Chemie International Edition, 36, 1374 (1997). [15] M. A. Dechanstreiter, E. Planker, B. Mathä, E. Lohof, G. Hölzemann, A. Jonczyk, S. L. Goodman, H. Kessler, Journal of Medicinal Chemistry, 42, 3033 (1999). [16] X. Chen, C. Plasencia, Y. Hou,. eamati, Journal of Medicinal Chemistry, 48, 1098 (2005). [17] Journal of Medicinal Chemistry, 48, 1098 (2005), and references therein. [18] K. Temming, R. M. Schiffelers, G. Molema, R. J. Kok, Drug Resistance Updates, 8, 381 (2005). [19] L. Colombo, M. Di Giacomo, G. Brusotti,. Sardone, M. Angiolini, L. Belvisi, S. Maffioli, L. Manzoni, C. Scolastico, Tetrahedron, 54, 5325 (1998). [20] L. Belvisi, L. Colombo, M. Colombo, M. Di Giacomo, L. Manzoni, B. Vodopivec, C. Scolastico, Tetrahedron, 47, 6463 (2001). [21] L. Colombo, M. Di Giacomo, V. Vinci, M. Colombo, L. Manzoni, Tetrahedron, 59, 4501 (2003). [22] L. Belvisi, A. Bernardi, L. Manzoni, D. Potenza, C. Scolastico, European Journal of rganic Chemistry, 2563 (2000). [23] Peptido-mimetic compounds containing RGD sequence useful as integrin inhibitors; and intermediate thereof, International Patent W 2005/ A1. [24] S. T. Diver, A. J. Giessert, Chemical Reviews, 104, 1317 (2004). [25] A. Hosomi, H. Sakurai, Tetrahedron Letters, 16, 1295 (1976). [26] R. H. Grubbs, Angewandte Chemie International Edition, 45, 3760 (2006). [27] S. B. Garber, J. S. Kingsbury, B. L. Gray, A. H. Hoveyda, Journal of the American Chemical Society, 122, 8168 (2000). [28] (a) Z. Xu, Y. Peng, T. Ye, rganic Letters, 16, 2821 (2003); (b) S. hira, Synthetic Communications, 19, 561 (1989). [29] M. Mori,. Sakakibara, A. Kinoshita, Journal of rganic Chemistry, 63, 6082 (1998). [30] S. J. Connon, S. Blechert, Angewandte Chemie International Edition, 42, 1900 (2003).
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