Synthesis and Evaluation of Linear and Macrocyclic Dolastatin 10 Analogues Containing Pyrrolidine Ring Modifications

AbstractThe five-membered pyrrolidine ring is one of the nitrogen heterocycles used widely by medicinal chemists to obtain compounds for the treatment of human diseases. The great interest in this saturated scaffold is enhanced by (1) the possibility to efficiently explore the pharmacophore space due to sp3-hybridization, (2) the contribution to the stereochemistry of the molecule, (3) and the increased three-dimensional (3D) coverage due to the non-planarity of the ring—a phenomenon called “pseudorotation”. In this review, we report bioactive molecules with target selectivity characterized by the pyrrolidine ring and its derivatives, including pyrrolizines, pyrrolidine-2-one, pyrrolidine-2,5-diones and prolinol described in the literature from 2015 to date. After a comparison of the physicochemical parameters of pyrrolidine with the parent aromatic pyrrole and cyclopentane, we investigate the influence of steric factors on biological activity, also describing the structure–activity relationship (SAR) of the studied compounds. To aid the reader’s approach to reading the manuscript, we have planned the review on the basis of the synthetic strategies used: (1) ring construction from different cyclic or acyclic precursors, reporting the synthesis and the reaction conditions, or (2) functionalization of preformed pyrrolidine rings, e.g., proline derivatives. Since one of the most significant features of the pyrrolidine ring is the stereogenicity of carbons, we highlight how the different stereoisomers and the spatial orientation of substituents can lead to a different biological profile of drug candidates, due to the different binding mode to enantioselective proteins. We believe that this work can guide medicinal chemists to the best approach in the design of new pyrrolidine compounds with different biological profiles.

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Pyrrolidine ring puckering in cis and trans-proline residues in proteins and polypeptides

Journal of Molecular Biology ◽

10.1016/0022-2836(92)90859-i ◽

1992 ◽

Vol 228 (3) ◽

pp. 725-734 ◽

Cited By ~ 97

Author(s):

E.James Milner-White ◽

Lachlan H. Bell ◽

Peter H. Maccallum

Keyword(s):

Pyrrolidine Ring ◽

Ring Puckering ◽

Cis And Trans ◽

In Cis

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(7-Chloro-2-oxo-2H-chromen-4-yl)methyl pyrrolidine-1-carbodithioate

Acta Crystallographica Section E Structure Reports Online ◽

10.1107/s1600536813028080 ◽

2013 ◽

Vol 69 (11) ◽

pp. o1684-o1685

Author(s):

O. Kotresh ◽

H. C. Devarajegowda ◽

Arunkumar Shirahatti ◽

K. Mahesh Kumar ◽

N. M. Mahabhaleshwaraiah

Keyword(s):

Hydrogen Bonds ◽

Dihedral Angle ◽

Title Compound ◽

Interplanar Spacing ◽

Ring System ◽

Maximum Deviation ◽

Pyrrolidine Ring ◽

Compound C ◽

Centroid Distance ◽

Chromene Ring

In the title compound, C15H14ClNO2S2, the 2H-chromene ring system is essentially planar, with a maximum deviation of 0.0133 (10) Å. Three C atoms and their attached H atoms of the pyrrolidine ring are disordered [occupany ratio 0.874 (7):0.126 (7)] with both disorder components adopting a twisted conformation. The dihedral angle between the 2H-chromene ring system and the major occupancy component of the pyrrolidine ring is 89.45 (7)°. In the crystal, inversion dimers linked by pairs of C—H...S and C—H...O interactions generateR22(24) andR22(10) loops, respectively. Further C—H...O hydrogen bonds link the dimers into [100] chains. C—H...π interactions also occur and there is very weak π–π stacking [interplanar spacing = 3.650 (5) Å; centroid–centroid distance = 4.095 (7) Å] between inversion-related chlorobenzene rings.

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Crystal structure of (1′S,2′S,3S)-1′-benzoyl-2′-(4-methoxyphenyl)-1-methyl-2′,5′,6′,10b′-tetrahydro-1′H-spiro[indoline-3,3′-pyrrolo[2,1-a]isoquinolin]-2-one

Acta Crystallographica Section E Crystallographic Communications ◽

10.1107/s2056989020010300 ◽

2020 ◽

Vol 76 (10) ◽

pp. 1548-1550

Author(s):

Janet Priyavathani Selvaraj ◽

Stella Mary ◽

Jyoti Boruah Dhruba ◽

Birkumar Singh Huidrom ◽

Yuvaraj Panneerselvam ◽

...

Keyword(s):

Crystal Structure ◽

Hydrogen Bonds ◽

Dihedral Angle ◽

Ring System ◽

Spiro Compound ◽

Pyrrolidine Ring ◽

Compound C ◽

C And N

In the title spiro compound, C34H30N2O3, the central pyrrolidine ring is fused with the tetrahydroisoquinoline ring, both having distorted envelope conformations, with the flap atoms being C and N, respectively. The methoxyphenyl group is attached to the pyrrolidine ring, and is disordered over two positions, with refined occupancies of 0.638 (6):0.362 (6) Å. The central pyrrolidine ring is inclined relative to the tetrahydroisoquinoline group, such that the dihedral between the non-flap atoms of each ring system is 11.29 (7)°. The spiro-linkage creates a dihedral angle of 83.26 (5)° between the indolinone ring and the non-flap atoms of the pyrrolidine ring. In the crystal, molecules are linked via C—H...O hydrogen bonds. For the major disorder component, these form C(11) chains that propagate parallel to the a axis.

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5′′-(4-Methoxybenzylidene)-1′-(4-methoxyphenyl)-1′′-methyl-1′,2′,3′,5′,6′,7′,8′,8a′-octahydrodispiro[acenaphthylene-1,3′-indolizine-2′,3′′-piperidine]-2,4′′(1H)-dione

Acta Crystallographica Section E Structure Reports Online ◽

10.1107/s1600536813001177 ◽

2013 ◽

Vol 69 (2) ◽

pp. o256-o257 ◽

Cited By ~ 2

Author(s):

J. Suresh ◽

R. A. Nagalakshmi ◽

S. Sivakumar ◽

R. Ranjith Kumar ◽

P. L. Nilantha Lakshman

Keyword(s):

Title Compound ◽

Chair Conformation ◽

The Other ◽

Piperidine Ring ◽

Pyrrolidine Ring ◽

Π Interactions ◽

Compound C ◽

The Mean ◽

Puckering Parameters ◽

Centrosymmetric Dimers

In the title compound, C39H38N2O4, the pyridinone ring adopts a twisted half-chair conformation with the N atom deviating by 0.3304 (1) and with the methylene C atom adjacent to the octahydroindolizine unit deviating by 0.444 (3) Å from the mean plane defined by the other four atoms. In the octahydroindolizine system, the pyrrolidine ring exhibits an envelope conformation, with the fused methyne C atom deviating by 0.6315 (1) Å from the mean plane defined by the other four atoms, and the piperidine ring exhibits a distorted chair conformation, as reflected in the puckering parametersQ= 0.568 (4) Å, θ = 1.5 (4) and ϕ = 161 (16)°. In the crystal pairs of weak C—H...O interactions form centrosymmetric dimers, which are further connected by C—H...π interactions. The crystal studied was a non-merohedral twin, with a domain ratio of 0.91:0.09.

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Pharmacokinetics of nefiracetam and three metabolites in humans and stereoselective hydroxylation of its pyrrolidine ring

Xenobiotica ◽

10.3109/00498259309059362 ◽

1993 ◽

Vol 23 (1) ◽

pp. 61-70 ◽

Cited By ~ 4

Author(s):

Y. Fujimaki ◽

K. Sudo ◽

H. Hakusui

Keyword(s):

Pyrrolidine Ring

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Crystal structure of ethyl (2S,2′R)-1′-benzyl-3-oxo-3H-dispiro[1-benzothiophene-2,3′-pyrrolidine-2′,11′′-indeno[1,2-b]quinoxaline]-4′-carboxylate

Acta Crystallographica Section E Crystallographic Communications ◽

10.1107/s2056989015003187 ◽

2015 ◽

Vol 71 (3) ◽

pp. o195-o196

Author(s):

J. Govindaraj ◽

R. Raja ◽

M. Suresh ◽

R. Raghunathan ◽

A. SubbiahPandi

Keyword(s):

Crystal Structure ◽

Three Dimensional ◽

Ring System ◽

Side Chain ◽

Dihedral Angles ◽

Pyrrolidine Ring ◽

Compound C ◽

Dimensional Network ◽

Centroid Distance ◽

Quinoxaline Ring

In the title compound, C35H27N3O3S, the spiro-linked five-membered rings both adopt twisted conformations. The pyrrolidine ring makes dihedral angles of 80.5 (1) and 77.4 (9)° with the benzothiophene ring system and the quinoxaline ring system, respectively. The S atom and C=O unit of the benzothiophene ring system are disordered over two opposite orientations in a 0.768 (4):0.232 (4) ratio. The atoms of the ethyl side chain are disordered over two sets of sites in a 0.680 (16):0.320 (16) ratio. In the crystal, molecules are linked by C—H...O, C—H...N and π–π interactions [shortest centroid–centroid distance = 3.4145 (19) Å], resulting in a three-dimensional network.

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