Bioorthogonal Prodrug Activation Driven by a Strain Promoted 1,3 Dipolar Cycloaddition
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1 Bioorthogonal Prodrug Activation Driven by a Strain Promoted 1,3 Dipolar Cycloaddition 1 Siddarth S. Matikonda, Douglas L. rsi, Verena Staudacher, Imogen A. Jenkins, Franziska Fiedler, Jiayi Chen and Allen B. Gamble Chemical Science, 2015, 6, pp (University of tago, Dunedin, New Zealand) A. Manos Turvey, Wipf Group Current Literature February 28 th, 2015 Alex Wipf Group Page 1 of 22 3/14/2015
2 Prodrugs for Cancer Therapies Non selectivity in cancer treatments leads to off target side effects Prodrug activation is seen as a viable method allowing for direct drug delivery Cleavage of a deactivating linker, leading to activation Can react with off target sources due to hydrolysis 2 Antibody Drug Conjugates (ADCs) ADCs can elicit an immune system response The linkers need to be fine tuned between stability and cleavability Drugs become diluted as this is dependant on cell surface receptors, leading to < potent R.V.J. Chari, M.L. Miller, W.C. Widdison, Angew. Chem., 2014, 53, Fig: seekingalpha.com/uploads/2014/1/ _ _1.jpg Alex Wipf Group Page 2 of 22 3/14/2015
3 Prodrugs for Cancer Therapies Antibody Directed Enzyme Prodrug Therapy (ADEPT) Targets an antibody enzyme conjugate to a cancer cell Limited to human enzymes, to avoid anti enzyme immune responses 3 K.D. Bagshawe, S.K. Sharma, R..J. Begent, Expert pin. Biol. Ther., 2004, 4, K. C. Chen, S. Y. Wu, Y. L. Leu, Z.M. Prijovich, B. M. Chen,. E. Wang, T. L. Cheng, S.R. Roffler, Bioconjugate Chem., 2011, 22, Alex Wipf Group Page 3 of 22 3/14/2015
4 Bioorthogonal Chemistry Prodrugs for Cancer Therapies Not many examples for in vitro prodrug activation 4 Staudinger and tetrazine TC (Inverse Electron Demand Diels Alder Cycloadditions) reactions have been used. K. Lang, J.W. Chin, Chem. Rev., 2014, Alex Wipf Group Page 4 of 22 3/14/2015
5 Bioorthogonal Chemistry Prodrugs for Cancer Therapies 5 TC/tetrazine prodrug activation difficulties: Lower TC conjugate activity Low tumour to background ADC ratio, leading to off target effects TC prodrug variant may isomerise to cis form if administered separately R.M. Versteegen, R. Rossin, W. ten oeve,.m. Janssen, M.S. Robillard, Angew. Chem. Int. Ed., 2013, 52, Alex Wipf Group Page 5 of 22 3/14/2015
6 Prodrugs for Cancer Therapies: 1,3 Dipolar Click Reaction with TC and Azide 6 Bioorthogonal Chemistry: TC and Azide First reported in 1992 Triazoline product is unstable K.J. Shea, J. S. Kim, J. Am. Chem. Soc., 1992, Alex Wipf Group Page 6 of 22 3/14/2015
7 Prodrugs for Cancer Therapies: 1,3 Dipolar Click Reaction with TC and Azide 6 Bioorthogonal Chemistry: TC and Azide First reported in 1992 Triazoline product is unstable K.J. Shea, J. S. Kim, J. Am. Chem. Soc., 1992, Alex Wipf Group Page 7 of 22 3/14/2015
8 Prodrugs for Cancer Therapies: 1,3 Dipolar Click Reaction with TC and Azide 7 TC and Azide for Prodrug Activation! Attach electron deficient linker to inactive drug TC identifies target Aqueous environment is key Alex Wipf Group Page 8 of 22 3/14/2015
9 Proof of Concept 8 Coumarin probes were synthesised to investigate rate and mechanism of reaction A doxorubicin azido PABC prodrug was synthesized to investigate in vitro biorthogonal activation N 3 Two TCs were made N 2 i) a) NaN 2,5MCl, 2 b) NaN 3, 2, 0 C ii) 4-N 2 PhC 2 Cl, pyridine, DCM, rt 2 N Et 3 N, DMF, rt 2 N 38% DIPEA, triphosgene, tol, reflux to rt 42% 30% N 3 N 8a 8b TC TC- N 3 doxorubicin.cl, Et 3 N, 4A sieves, DMF, rt 69% N 3 9 N Alex Wipf Group Page 9 of 22 3/14/2015
10 Tested by spectrofluorometry, measuring fluorescence (ex 360 nm, em 455 nm) N 3 in PBS:MeCN (1:1) n=3 Proof of Concept 9 8a N 3 N 8b 2 N Alex Wipf Group Page 10 of 22 3/14/2015
11 Mechanism A series of 1 NMR experiments were then carried out 8a carbonate was used at 6.7 mm, TC at 18.7 mm 10 Alex Wipf Group Page 11 of 22 3/14/2015
12 Mechanism 11 #! * Alex Wipf Group Page 12 of 22 3/14/2015
13 Mechanism 12 #! $ * Alex Wipf Group Page 13 of 22 3/14/2015
14 Rate of Reaction of 1,3 Dipolar Cycloaddition TC/TC activation results in coumarin release RP PLC was used to determine the second order rate of the initial 1,3 dipolar cycloaddition MeCN:PBS (1:1, 37 C), measuring disappearance of SM at 254 nm Comparable rates to those seen with first generation SPAAC ( M 1 s 1 ) 13 N 3 TC- eq k 2 = M -1 s -1 N N N 8a triazoline TC- ax k 2 = M -1 s -1 K.J. Shea, J. S. Kim, J. Am. Chem. Soc., 1992, Alex Wipf Group Page 14 of 22 3/14/2015
15 Rate of Reaction for Coumarin Release 8b and TC were reacted in CD 3 CN and DMS d 6 for 19 h to give 11b An aliquot of the NMR was then diluted into PBS and the rate of triazoline and imine degradation was monitored spectroscopically by the appearance of 13b 14 Alex Wipf Group Page 15 of 22 3/14/2015
16 Rate of Reaction for Coumarin Release 8b and TC were reacted in CD 3 CN and DMS d 6 for 19 h to give 11b An aliquot of the NMR was then diluted into PBS and the rate of triazoline and imine degradation was monitored spectroscopically by the appearance of 13b 15 Alex Wipf Group Page 16 of 22 3/14/2015
17 Rate of Reaction for Coumarin Release 8b and TC were reacted in CD 3 CN and DMS d 6 for 19 h to give 11b An aliquot of the NMR was then diluted into PBS and the rate of triazoline and imine degradation was monitored spectroscopically by the appearance of 13b 15 Alex Wipf Group Page 17 of 22 3/14/2015
18 Rate of Reaction for Coumarin Release 16 N N N N 11b - triazoline ii) dilute 1000-fold into PBS 2 N 13b t 1/2 =19min Degradation and release (3 steps) follows pseudo first order kinetics in polar protic solvents Assumption that either triazoline degradation or imine hydrolysis is the rate limiting step In vivo this rate is less significant as both intermediates will be fixed to a cancer cell surface Alex Wipf Group Page 18 of 22 3/14/2015
19 Bioorthogonal Potential 17 Compound IC 50 (µm) N 3 N TC- (10) doxorubicin (15) pro drug CC (100 µm) TC (mix) (100 µm) TC (eq) (100 µm) N N doxorubicin 9 + TC (ax) (100 µm) TC (eq) (10 µm) 4.98 Using a model murine melanoma cell line (B16 VA), the reaction strategy was evaluated in vitro following 72 h incubation with 9 and 10 at 37 C 9 cytotoxicity alone is low The authors propose that 15 is released outside of targeted tumour cells and then diffuses into the closely located cancer cells Alex Wipf Group Page 19 of 22 3/14/2015
20 Bioorthogonal Potential Attachment of 1 6 TCs to each monoclonal antibody with binding with 10 5 cell surface receptors, [TC] = µm on tumour cell surfaces 9 rate of reaction still needs improvement 18 Need to overcome rapid clearance rates from mice (t 1/2 = mins) for similar compounds In vivo suitability was evaluated by monitoring stability and activation of 9 in 50% mouse serum:pbs and PBS only (PLC analysis) Time (h) Degradation of 9 (15 release) PBS only PBS + MS Degradation of 9 (15 release) + TC eq PBS only PBS + MS 0 100% (0%) 100% (0%) 100% (0%) 100% (0%) 4 106% (0%) 95% (0%) 84% (34%) 47% (51%) % (0%) 68% (0%) 39% (77%) 12% (59%) % (0%) 56% (6%) 12% (79%) 2% (5%) Alex Wipf Group Page 20 of 22 3/14/2015
21 Bioorthogonal Potential No reaction deactivation from serum derived byproducts 19 a problem seen with Staudinger prodrug activations Investigated if serum protein interactions may reduce effective [9] and therefore activity SPAAC cyclooctyne reactants (added after tumour targeting) interact with serum and show reduced in vivo reaction rates The reaction proceeds faster in the presence of serum than the model systems of 8a and 8b in MeCN:PBS (k 2 = M 1 s 1 ) TC- (10) k 2 = M -1 s -1 N 3 N 50% serum:pbs 15 - doxorubicin N 2 9 Alex Wipf Group Page 21 of 22 3/14/2015
22 Successfully use a 1,3 dipolar cycloaddition between TC and an azide, to facilitate prodrug activation Activation is 1 2 orders of magnitude faster than the Staudinger reaction variants (and faster still in serum:pbs mixtures TC could isomerise, but will be modified with antibody linkers known to stabilise isomerization Still room to expand on reactivity through modification of the azido prodrug Good stability in mouse serum (min to h) Conclusions and Scope Next step: need to move from the hypothetical to the actual prodrug antibody system 22 Alex Wipf Group Page 22 of 22 3/14/2015
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