Selectively Modified Cobyrinic Acid Derivatives

Proinsias, Keith ó; Giedyk, Maciej; Banach, Łukasz; Rutkowska‐Zbik, Dorota; Gryko, Dorota

doi:10.1002/ajoc.201300051

Cited by 2 publications

(7 citation statements)

References 33 publications

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“…We recently reported the selective synthesis of novel cobinamide derivatives starting from heptamethyl cobyrinate ( 1 ) 13. 14 A small library of various heptaamides was obtained, among which hydrophilic product 2 , bearing seven ethanolamide residues, displayed the highest activity toward sGC (Scheme ).…”

Section: Resultsmentioning

confidence: 99%

“…Ester 5 was treated with NaOH, and after acidification was extracted with phenol. In turn, monoamide 7 was transformed into hexaamide 8 by treating with excess 2‐aminoethanol in the presence of DBU/benzotriazole 14…”

Section: Resultsmentioning

confidence: 99%

“…Preparation of hexaamide 8 . Following the reported procedure,14 product 8 was isolated as a purple solid (11 mg, 65 %): R f =0.24 (MeOH/CH 2 Cl 2 40 %); 1 H NMR (500 MHz, [D 6 ]DMSO): δ =8.42 (t, J =5.9 Hz, 1 H), 8.38 (t, J =5.5 Hz, 1 H), 8.10 (t, J =5.5 Hz, 1 H), 7.96 (t, J =5.5 Hz, 1 H), 7.89 (t, J =5.5 Hz, 1 H), 7.60 (t, J =5.5 Hz, 1 H), 5.56 (s, 1 H), 4.90–4.82 (m, 2 H), 4.67 (bs, 3 H), 4.55 (bs, 1 H), 4.37 (d, J =8.7 Hz, 1 H), 3.69 (d, J =17.8 Hz, 1 H), 3.60 (d, J =10.5 Hz, 1 H), 3.48–3.35 (m, 13 H including residual Et 2 O), 3.26–3.00 (m, 14 H), 3.83–3.73 (m, 2 H), 2.66–2.61 (m, 1 H), 2.45–2.34 (m, 3 H), 2.31–2.24 (m, 1 H), 2.23–2.13 (m, 9 H), 2.10–1.97 (m, 5 H), 1.91 (bs, 1 H), 1.82–1.71 (m, 3 H), 1.66–1.58 (m, 2 H), 1.49 (s, 3 H), 1.33 (s, 3 H), 1.30 (s, 3 H), 1.22 (s, 3 H), 1.13 (s, 3 H), 1.11–1.03 ppm (m, 9 H including residual Et 2 O); 13 C NMR (125 MHz, [D 6 ]DMSO): δ =175.7, 175.5, 175.3, 172.4, 171.29, 171.25, 170.7, 170.6, 169.3, 167.8, 164.1, 162.5, 102.9, 101.5, 82.4, 74.9, 64.8, 62.0, 59.81, 59.76, 59.7, 59.5, 58.0, 56.0, 55.0, 52.8, 48.2, 46.0, 45.9, 45.0, 42.0, 41.8, 41.6, 41.54, 41.49, 40.0, 39.83, 39.76, 39.7, 39.6, 39.5, 39.3, 39.2, 39.0, 38.5, 35.5, 32.2, 32.0, 31.0, 30.8, 25.4, 23.7, 21.7, 19.3, 18.5, 17.7, 16.0 ppm; UV/Vis (MeOH): λ max ( ε )=578 (8.83×10 3 ), 538 (7.75×10 3 ), 367 (2.53×10 4 ), 308 (9.43×10 3 ), 276 nm (1.10×10 4 ); HRMS‐ESI ( m / z ) [ M +Na] + calcd for C 56 H 85 CoN 12 O 12 Na: 1199.6540, found: 1199.5634; Anal. calcd for C 56 H 85 CoN 12 O 12 +5 H 2 O: C 53.07, H 7.56, N 13.26, found: C 53.05, H 7.46, N 13.22.…”

Section: Methodsmentioning

confidence: 99%

“…Preparation of compound 15 . Following the reported procedure,14 product 15 was isolated as a purple solid (56 mg, 54 %): R f =0.55 (EtOH/CH 2 Cl 2 10 %); mp: 130 °C; 1 H NMR (500 MHz, [D 6 ]acetone): δ =6.88 (t, J =5.2 Hz, 1 H), 5.77 (s, 1 H), 3.95 (d, J =9.4 Hz, 1 H), 3.95 (d, J =9.2 Hz, 1 H), 3.74 (s, 3 H), 3.71–3.64 (m, 10 H), 3.58 (s, 3 H), 3.40–3.37 (m, 2 H), 3.253 (t, J =5.5 Hz, 1 H), 3.12–3.09 (m, 2 H), 3.07 (s, 1 H), 2.94–2.89 (m, 2 H), 2.84–2.80 (m, 1 H), 2.72–2.65 (m, 2 H), 2.63–2.44 (m, 6 H), 2.42–2.22 (m, 11 H), 2.20–1.15 (m, 1 H), 2.12–2.07(m, 2 H), 1.91–1.79 (m, 3 H), 1.76 (s, 3 H), 1.53 (s, 3 H), 1.47 (s, 3 H), 1.45 (s, 3 H), 1.32 (s, 3 H), 1.17 ppm (s, 3 H); 13 C NMR (125 MHz, [D 6 ]acetone): δ =179.3, 177.2, 176.6, 174.1, 173.28, 173.27, 173.1, 173.0, 172.6, 172.0, 167.2, 163.9, 161.2, 105.0, 104.9, 95.8, 88.6, 83.8, 76.1, 61.9, 61.7, 59.3, 57.7, 54.3, 52.5, 52.1, 52.0, 51.8, 51.7, 51.0, 48.2, 46.7, 43.3, 43.1, 43.0, 42.93, 42.90, 41.9, 40.4, 34.0, 33.0, 32.6, 32.0, 31.4, 30.9, 30.6, 30.3, 30.1, 30.0, 29.8, 29.7, 29.5, 29.3, 26.5, 25.5, 23.3, 22.6, 19.8 ppm; UV/Vis (CH 2 Cl 2 ): λ max (ε)=592 (1.20×10 4 ), 553 (1.02×10 4 ), 369 (3.15×10 4 ), 318 (9.97×10 3 ), 230 nm (3.74.x10 4 ); HRMS‐ESI ( m / z ) [ M +Na] + calcd for C 54 H 72 CoN 7 O 14 Na: 1124.4367, found: 1124.4398; Anal. calcd for C 54 H 72 CoN 7 O 14 : C 58.85, H 6.58, N 8.90, found: C 58.77, H 6.81, N 8.67.…”

Section: Methodsmentioning

confidence: 99%

“…Preparation of c ‐acid derivative 16 . Following the reported procedure,14 product 16 was crudely purified and used as a purple solid without further purification. HRMS‐ESI ( m / z ) [ M −CN] + calcd for C 53 H 74 CoN 6 O 14 : 1077.4595, found: 1077.4596.…”

Section: Methodsmentioning

confidence: 99%

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Small Alterations in Cobinamide Structure Considerably Influence sGC Activation

et al. 2014

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Specially designed B-ring-modified cobalamin derivatives were synthesized and tested as potential activators of soluble guanylyl cyclase (sGC). Herein, we disclose the influence of substituents at the c- and d-positions in hydrophilic and hydrophobic cobyrinic acid derivatives on their capacities to activate sGC. The presence of the amide group at c-/d-position in cobyrinic acid derivatives strongly influence the level of sGC activation. Removal of the d-position altogether has a profound effect for hydrophobic compounds. In contrast, little differences were observed in hydrophilic ones.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Small Alterations in Cobinamide Structure Considerably Influence sGC Activation

et al. 2014

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Synthesis and Evaluation of Bifunctional sGC Regulators: Optimization of a Connecting Linker

et al. 2013

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Hybrid molecules composed of PpIX and cobyrinic acid derivatives conjugated through linkers of varying length and composition were prepared via 1,3-dipolar cycloaddition (CuAAC) or amidation/esteryfication reactions. They were tested for activation of soluble guanylyl cyclase (sGC), a key enzyme in the NO/cGMP signaling pathway, by an in vitro GTP→cGMP conversion assay. Using purified heme-deficient sGC and truncated sGC variants lacking a heme-binding domain, we demonstrated that such hybrid molecules may activate sGC by targeting heme-binding and/or catalytic domain. While all conjugates activated sGC, only selected compounds served as bifunctional regulators and were capable of simultaneous targeting both heme and catalytic domains of sGC. The length and type of a linker connecting both components had a profound effect on the extent of sGC activation, indicating that the linker's type is crucial for their binding affinities with regulatory and catalytic domains. Only hybrids with the conjugated linker of 13-16 atom length synergistically target both domains and displayed the lowest EC50 and highest activating potency. Compounds with shorter connecting linkers were much less potent and were no more active than the cobyrinic acid component alone. The most active conjugate, which showed a 60-fold activation of sGC, was compound 11, in which PpIX and cobyrinic acid components are separated by 11 atoms chain with the triazole moiety in between.

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Selectively Modified Cobyrinic Acid Derivatives

Cited by 2 publications

References 33 publications

Small Alterations in Cobinamide Structure Considerably Influence sGC Activation

Small Alterations in Cobinamide Structure Considerably Influence sGC Activation

Synthesis and Evaluation of Bifunctional sGC Regulators: Optimization of a Connecting Linker

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