Applications of ferrocene-peptide conjugates : towards new biosensors and materials

Ferrocene-peptide conjugates represent a hybrid area between organometallic chemistry and biochemistry.In these bioconjugates, the ferrocene (Fc) moiety can serve as molecular scaffold, chromophore, sensitive probe, biological marker, redox active site, etc. Disubstituted Fc systems, in which both cyclopentadienyl rings are substituted, provide influence over the supramolecular structure of the assemblies, and serve as starting materials for the design of electronic biomaterials.Recently, 1'amino-ferrocene-1-carboxylic acid (Fca) and 1,1'-diaminoferrocene Fc[NH 2 ] 2 were recognized as useful tools in bioorganometallic chemistry.This work sketches some novel preparative and structural aspects of Fc-peptide conjugates and explores their applications as biosensors and as polymeric materials.First, I demonstrated that Fca invariably induces a turn-like structure, which is stable in solution and the solid state.The obtained results showed different behaviour for Fca peptides depending on the chirality and position of the attached amino acid.The axial chirality of the Fca is completely dependent on the chirality of the first amino acid attached to the amino terminal of the Fca group.Second, I was able to develop a surface based sensor for the electrochemical detection of papain based on Fc-peptide conjugates.The idea was to place a surfacebound redox probe in close proximity to the electrode surface.In addition, the redoxactive Fca label will be part of the recognition site but will not interfere with the recognition process.My sensor provides an attractive alternative for the electrochemical detection of non-labelled non-redox active proteins, which under current detection schemes remains a significant challenge.No. Scheme 1.1.Synthesis of ferrocenoyl amino acid esters (5) via the acid chloride and active ester methods: (i) (COCl) 2 or SOCl 2 ; (ii) carbodiimide such as DCC or EDC, HOBt; (iii) carbodiimide such as DCC or EDC, HOSu and (iv) peptide or amino acid and base...... 4 Scheme 1.2.Synthesis of 1,1'-bispeptide Fc derivatives peptides 7 -13 via the HOBt/EDC protocol: (i) HOBt, EDC, CH 2 Cl 2 , H-Pro n -OMe (n = 1-4) 5 Scheme 1.3.Unusual synthesis of Fc[Val-OMe] 2 15 from the Li salt of CP-Val-OMe 14 formed by the addition of isocyanate: (i) FeCl 2 , THF, 60C, 7d; (ii) FeCl 2 /CpLi, 50 C, THF, 7d. 6 Scheme 1.4.Synthesis of redox active cyclopeptides : (i) EDC, HOBt, CH 2 Cl 2 ; (ii) (CSA) 2 2HCl, CH 2 Cl 2 ; (iii) a) Boc-amino acid CSA dimer, TFA; b) Et 3 N, CH 2 Cl 2 ; (iv) dilution.......... 7 Scheme 1.5.Synthesis of Boc-protected 1'-aminoferrocene-1-carboxylic acid.(i) t-BuOH, reflux for 4 hours (ii) NaOH/H 2 O, MeOH (iii) TFA/CH 2 Cl 2 .. 8 Scheme 1.6.Synthesis of Fc amino acid hydrochloride 27 according to Heinze: (i) N-acetylation with Ac 2 O, (ii) selective Friedel-Crafts acylation with 2,6-dichlorobenzoyl chloride at the unsubstituted Cp ring; (iii) base hydrolysis; (iv) removal of the acetyl protection group with hydrochloric acid... 9 Scheme 1.7.Synthesis of the tetrapeptide Boc-Ala-Fca-Ala-Ala-OMe 29 derived from 1'-Boc-aminoferrocene-1-carboxylic (Fca) 23a: (i) + H-Ala-Ala-OMe, EDC/HOBt; (ii) HCl(g)/ AcOEt; + Boc-Ala-OH,EDC/HOBt.. 10 Scheme 1.8.(a) Reaction of 38b with the alkylating reagents to form compounds 30-33 (b) synthesis of compound 34 from 23a according to Khan et al. (i) EtOH (ii) Saturated NaHCO 3 (iii) HOBt, EDC (iv) Cystamine, Et 3 N. .11 Scheme 1.9.Arnold's synthesis of 1,1'-diaminoferrocene involving the explosive diazidoferrocene: (i) C 2 H 2 Br 4 , Et 2 O, (ii) NaN 3 , CuI, EtOH/H 2 O, (iii) H 2 , Pd/C, MeOH. 12 Scheme 1.10.Synthesis of 1,1-bis(Boc-amino)ferrocene 40 via 1,1bis(carbonylazido) Fc 39, and its amino acid derivatives with L-Ala (41a) and D-Ala (41b).(i) Reflux in t-BuOH, 80 C, 8 h; (ii) a) TFA, b) TEA, c) Boc-Ala-OH activated by EDC/HOBt. 12 xix Scheme 1.11.Torsion angles in Fc-amino acids and peptides: = Cp bent and = twist between amide and Cp planes Scheme 1.12.Some of the possible orientation of the amino acid and peptide substituents.Structure a) is the most commonly found structural motif having the two C=O anti orientation.Scheme 1.13.Synthesis of the methylsiloxane polymer [-Si-(CH 3 ) 2 -(CH 2 ) 3 -NHC(O)-Fc-C(O)NH(CH 2 ) 3 Si(CH 3 ) 2 O-] n 50 having Fc in the backbone of the polymer chain.. Scheme 1.14.Synthesis of cyclopeptides 51 and 52 by condensation of 1,1'ferrocenyldicarbonyl chloride and bifunctional cystein derivatives Scheme 1.15.Synthesis of some Fc-containing aromatic polyamides 53... Scheme 1.16.Preparation of some Fc-based poly(amide ether amide)s 54 Scheme 1.17.Structure of the organometallic Fc-polypeptide proposed by Nakamura..... Scheme 1.18.Coupling of ferrocenoyl benzotriazole ester 55 with aminoferrocene 24 to give the diferrocenyl diamide 56; (i) THF, 12 h.. Scheme 1.19.Synthesis of P-and M-helical foldamers from the conjugates of Fca with L-and D-alanine resulted in the formation of the oligomers 57-64 and the polymer 65... Scheme 1.20.Synthesis of elastomeric polyamides 67 and 68 from 1,1'-bis(aminoethyl) Fc 66 and diacid chlorides.(i) Cl-CO-R-CO-Cl; (ii) OCN-R'-NCO............

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