Amido‐Functionalised Prodigiosenes: Synthesis and Anticancer Properties

Díaz, Rosa I. Sáez; Bennett, Sarah M.; Thompson, Alison

doi:10.1002/cmdc.200900003

Cited by 22 publications

(14 citation statements)

References 33 publications

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“…Similarly, several homoleptic zinc complexes of pyrrolyldipyrrins, such as 2 (Chart 1), 22,23,37 share the characteristics of other complexes within the large family of simple dipyrrins, which coordinate as bidentate monoanionic ligands. The additional pyrrolic ring on the prodigiosin-type scaffolds behaves as a ligand in fluorescent dialkyl and diaryl tin(IV) complexes such as 3 (Chart 1), 38 for which structural characterization revealed tridentate coordination of all nitrogen donors on the fully conjugated pyrrolyldipyrrin scaffold.…”

Section: Introductionmentioning

confidence: 99%

Prodigiosin Analogue Designed for Metal Coordination: Stable Zinc and Copper Pyrrolyldipyrrins

et al. 2014

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The pyrrolyldipyrrin motif is found in several naturally occurring prodigiosin pigments. The potential roles of the interactions of prodigiosins with transition metals and the properties of metal-bound pyrrolyldipyrrins, however, have been difficult to assess because of the very limited number of well-characterized stable complexes. Here, we show that the introduction of a meso-aryl substituent and an ethyl ester group during the sequential assembly of the three heterocycles affords a pyrrolyldipyrrin of enhanced coordinating abilities when compared to that of natural prodigiosins. UV–visible absorption studies indicate that this ligand promptly binds Zn(II) ions with 2:1 ligand-to-metal stoichiometry and Cu(II) ions with 1:1 stoichiometry. Notably, no addition of base is required for the formation of the resulting stable complexes. The crystal structures reveal that whereas the tetrahedral zinc center engages two nitrogen donors on each ligand, the pseudosquare planar copper complex features coordination of all three pyrrolic nitrogen atoms and employs the ester group as a neutral ligand. This first example of coordination of a redox-active transition metal within a fully conjugated pyrrolyldipyrrin framework was investigated spectroscopically by electron paramagnetic resonance to show that the 1:1 metal-to-ligand ratio found in the crystal structure is also maintained in solution.

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Section: Introductionmentioning

confidence: 99%

Prodigiosin Analogue Designed for Metal Coordination: Stable Zinc and Copper Pyrrolyldipyrrins

et al. 2014

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“…The crude mixture was puried by column chromatography using Al 2 O 3 type III neutral (EtOAc 100%) followed by Al 2 O 3 type III neutral (CH 2 Cl 2 : MeOH 99 : 1) and Al 2 O 3 type III basic (CH 2 Cl 2 : MeOH 99.5 : 0.5, 99 : 1, 98.5 : 0.5) to afford 8c as a red glass (0.116 g, 63%). 1 13 (Z)-tert-Butyl (24-(2-((4-methoxy-1H,1 0 H-[2,2 0 -bipyrrol]-5-yl) methylene)-3,5-dimethyl-2H-pyrrol-4-yl)-15,24-dioxo-4,7,10trioxa-14-azatetracosyl)carbamate (9c). Compound 9c was obtained according to GP1.…”

Section: General Procedures 1 (Gp1)mentioning

confidence: 99%

“…The crude mixture was puried by column chromatography using Al 2 3.92 (s, 3H), 6.08 (s, 1H), 6.25-6.27 (m, 1H), 6.76-6.78 (m, 2H), 7.02-7.03 (m, 1H). 13 (Z)-N-(2-Aminoethyl)-10-(2-((4-methoxy-1H,1 0 H-[2,2 0 -bipyrrol]-5-yl)methylene)-3,5-dimethyl-2H-pyrrol-4-yl)-10oxodecanamide (2c). A solution of 8c (0.073 g, 0.12 mmol) in a mixture of CHCl 3 : MeOH (1 : 1, 6 mL) was treated with HCl 12 N (0.024 mL, 0.29 mmol) and the reaction mixture was stirred at room temperature for 7 h. The solvent was removed under vacuum and NaOH (10% aq.…”

Section: General Procedures 1 (Gp1)mentioning

confidence: 99%

“…5 Known mechanisms of bioactivity include H + /Cl À exchange, oxidative DNA cleavage through Cu(II) chelation and signal-transduction interference. [6][7][8][9][10][11][12][13][14][15] Synthetic mimics of prodigiosin, named prodigiosenes, 16 with modications on the A-, B-or C-ring [17][18][19][20][21][22][23][24] have been shown to maintain the biological activity of the parent compound yet with 100-fold improvements in selectivity towards malignant cells and with 100-fold reduction of systemic toxicity in mice compared to the natural product (R ¼ CO 2 iPr, R 1 ¼ Me, Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

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A step-wise synthetic approach is necessary to access γ-conjugates of folate: folate-conjugated prodigiosenes

et al. 2019

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Despite the vast literature that describes reacting folic acid with a pharmacophore, this route is ineffective in providing the correct regioisomer of the resulting conjugate. We herein present a step-wise route to the preparation of nine folate conjugates of the tripyrrolic prodigiosene skeleton. The strict requirement for step-wise construction of the folate core is demonstrated, so as to achieve conjugation at only the desired g-carboxylic acid and thus maintain the a-carboxylic site for folate receptor (FRa) recognition.Linkages via ethylenediamine, polyethylene glycol and glutathione are demonstrated.

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“…HRMS (ESI + ): m/z calcd for C 15 H 18 BrN 2 O 3 [M + ]: 353.0495; found: 353.0482. Procedure for the Synthesis of Prodigiosenes (1) Compound 7a (3.20 g, 9.06 mmol), LiCl (1.16 g, 27.36 mmol), 1-N-Boc-pyrrole-2-boronic acid (2.32 g, 10.99 mmol), and Pd(PPh 3 )4 (1.05 g, 0.91 mmol) were dissolved in 1,2-dimethoxyethane (180 mL), and the solution was purged by bubbling with nitrogen for 10 min. A solution of Na 2 CO 3 (2 M, 18.2 mL, 36.4 mmol) was then added, and the reaction mixture was stirred at 85°C for 24 h. After cooling to r.t. the reaction mixture was poured into H 2 O.…”

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confidence: 99%

Improved Synthetic Route to C-Ring Ester-Functionalized Prodigiosenes

Uddin¹,

Thirumalairajan²,

Crawford³

et al. 2010

Synlett

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An efficient, optimized, and scalable process for the synthesis of C-ring ester-functionalized prodigiosenes has been developed by (i) exploiting a silylative Mukaiyama aldol strategy for the condensation of alkyl 5-formyl-2,4-dimethylpyrrole-3-carboxylate and 4-methoxy-3-pyrrolin-2-one to form the corresponding esterfunctionalized dipyrrinone analogues, and (ii) developing a facile synthesis of stable bromodipyrrin analogues for the use in formal Suzuki coupling reactions. The process was applied to the synthesis of three C-ring ester-functionalized prodigiosenes in multigram scales (up to 6.5 g prodigiosene free-base) with useful yields (35-56% overall yields over three steps starting from the 2-formyl pyrroles).Prodigiosenes belong to a family of tripyrrolic red pigments with important biological properties. 1 Thus several investigations have been focused on the structure-activity relationships in prodigiosenes. 2 Recently, we have discovered that C-ring functionalized prodigiosenes exhibit efficient anticancer properties in effective doses. 3,4 These discoveries stimulated the development of an expedient synthetic strategy to prepare novel analogues with potent anticancer properties ( Figure 1) and to prepare highly active derivatives on a multigram scale. Figure 1 C-Ring ester-functionalized prodigiosenesTwo main synthetic strategies for the synthesis of the tripyrrolic skeleton of prodigiosenes have been reported: (i) the condensation of a bipyrrole unit with the C-ring moiety (path A and path B, Scheme 1), 5,6 and (ii) the coupling of a dipyrrin unit with the A-ring (path C, Scheme 1). 7 Path A suffered from low yields as the bipyrrolic unit was consistently synthesized using a low yielding McFayenStevens reduction. 5 An alternative strategy to generate the bipyrrolic unit was recently developed by Dairi et al. (path B, Scheme 1) and involves the synthesis of a 2-formyl bipyrrole in a two-step route from 4-methoxy-3-pyrrolin-2-one. 8,9 Unfortunately, this process was not successful in our hands as the 2-formyl bipyrrole could only be isolated in low and irreproducible yields.Path C is relatively more convenient and has traditionally relied on a base-promoted condensation of a 2-formyl pyrrole with a pyrrolin-2-one to generate the dipyrrinone unit, followed by formation of the triflated analogues and then Suzuki coupling to the final pyrrolyl-dipyrrin skeletons. 3 However, the base-promoted condensation step of this process to generate the dipyrrinones suffers serious limitations due to the equilibrium between the retro 2-formyl pyrrole in the presence of strong base, as observed by others during the synthesis of metacycloprodigiosin. 10 Once synthesized, the dipyrrinone is converted into a triflate analogue, which, depending on the substituent at R 1 , has limited thermal stability. The low thermal stability of these analogues renders purification of multigram quantities problematic.As part of our studies towards mapping the SAR profile of C-ring ester-functionalized prodigiosenes with optimized immunosup...

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Amido‐Functionalised Prodigiosenes: Synthesis and Anticancer Properties

Cited by 22 publications

References 33 publications

Prodigiosin Analogue Designed for Metal Coordination: Stable Zinc and Copper Pyrrolyldipyrrins

Prodigiosin Analogue Designed for Metal Coordination: Stable Zinc and Copper Pyrrolyldipyrrins

A step-wise synthetic approach is necessary to access γ-conjugates of folate: folate-conjugated prodigiosenes

Improved Synthetic Route to C-Ring Ester-Functionalized Prodigiosenes

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