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Synthesis and biological activities of (R)- and (S)-N-(4-Methoxyphenyl)-N,2,6-trimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-aminium chloride as potent cytotoxic antitubulin agents.

ABSTRACT: (R,S)-1 is a potent antimitotic compound. (R)-1·HCl and (S)-1·HCl were synthesized from (R)- and (S)-3-methyladipic acid. Both enantiomers were potent inhibitors of cell proliferation and caused cellular microtubule loss and mitotic arrest. They inhibited purified tubulin assembly and the binding of [(3)H]colchicine to tubulin, with (S)-1 being about twice as potent. Cytotoxicity against 60 tumor cell lines, however, indicated that the (S)-isomer was 10- to 88-fold more potent than the (R)-isomer.

SUBMITTER: Gangjee A

PROVIDER: S-EPMC3184787 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Synthesis and biological activities of (R)- and (S)-N-(4-Methoxyphenyl)-N,2,6-trimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-aminium chloride as potent cytotoxic antitubulin agents.

Gangjee Aleem A Zhao Ying Y Hamel Ernest E Westbrook Cara C Mooberry Susan L SL

Journal of medicinal chemistry 20110805 17

(R,S)-1 is a potent antimitotic compound. (R)-1·HCl and (S)-1·HCl were synthesized from (R)- and (S)-3-methyladipic acid. Both enantiomers were potent inhibitors of cell proliferation and caused cellular microtubule loss and mitotic arrest. They inhibited purified tubulin assembly and the binding of [(3)H]colchicine to tubulin, with (S)-1 being about twice as potent. Cytotoxicity against 60 tumor cell lines, however, indicated that the (S)-isomer was 10- to 88-fold more potent than the (R)-isome ...[more]

PMID: 21786793

Similar Datasets

Structure-activity relationship and in vitro and in vivo evaluation of the potent cytotoxic anti-microtubule agent N-(4-methoxyphenyl)-N,2,6-trimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-aminium chloride and its analogues as antitumor agents.

Project description:A series of 21 substituted cyclopenta[d]pyrimidines were synthesized as an extension of our discovery of the parent compound (±)-1·HCl as an anti-microtubule agent. The structure-activity relationship indicates that the N-methyl and a 4N-methoxy groups appear important for potent activity. In addition, the 6-substituent in the parent analogue is not necessary for activity. The most potent compound 30·HCl was a one to two digit nanomolar inhibitor of most tumor cell proliferations and was up to 7-fold more potent than the parent compound (±)-1·HCl. In addition, 30·HCl inhibited cancer cell proliferation regardless of Pgp or βIII-tubulin status, both of which are known to cause clinical resistance to several anti-tubulin agents. In vivo efficacy of 30·HCl was demonstrated against a triple negative breast cancer xenograft mouse model. Compound 30·HCl is water-soluble and easily synthesized and serves as a lead compound for further preclinical evaluation as an antitumor agent.

| S-EPMC3850778 | biostudies-literature

3,9-Dibromo-6,7-dihydro-5H-dibenzo[c,e]thiepine.

Project description:In the title mol-ecule, C(14)H(10)Br(2)S, the two benzene rings form a dihedral angle of 48.35 (14)°. The seven-membered ring adopts a boat conformation. In the crystal structure, mol-ecules are related by translation along the b axis and exhibit C-H⋯π inter-actions.

| S-EPMC2961378 | biostudies-literature

6-Benzyl-6,7-dihydro-5H-pyrrolo-[3,4-b]pyridine-5,7-dione.

Project description:In the title compound, C(14)H(10)N(2)O(2), the dihedral angle between the heterocyclic ring system and the phenyl ring is 45.8?(5)°. Weak inter-molecular C-H?N hydrogen bonding is present in the crystal structure.

| S-EPMC3247312 | biostudies-literature

Efficient Synthesis of 6,7-Dihydro-5H-cyclopenta[b]pyridine-3-carbonitrile Compounds and Their Applicability As Inhibitor Films for Steel Alloy Corrosion: Collective Computational and Practical Approaches.

Project description:An effective method for designing new heterocyclic compounds of 6,7-dihydro-5H-cyclopenta[b]pyridine-3-carbonitrile derivatives (CAPDs) was presented through cyclocondensation reaction between 2,5-diarylidenecyclopentanone derivatives and propanedinitrile, and the cyclocondensation reaction succeeded using a sodium alkoxide solution (sodium ethoxide or sodium methoxide) as the reagent and the catalyst. The synthesized CAPD derivatives were employed as novel inhibitors for carbon steel (CS) corrosion in a molar H2SO4 medium. The corrosion protection proficiency was investigated by electrochemical measurements (open circuit potential vs time (E OCP vs t), potentiodynamic polarization plots (PDP), and electrochemical impedance spectroscopy (EIS)) and surface morphology (scanning electron microscopy (SEM)) examinations. The results show that the CAPD derivatives exhibit mixed type inhibitors and a superior inhibition efficiency of 97.7% in the presence of 1.0 mM CAPD-1. The adsorption of CAPD derivatives on the CS interface follows the Langmuir isotherm model, including physisorption and chemisorption. Scanning electron microscopy (SEM) exploration confirmed the adsorption of the CAPD derivatives on the CS substrate. Monte Carlo (MC) simulations and DFT calculations revealed that the efficacy of the CAPD molecules correlates well with their structures, and this protection was attributed to their adsorption on the CS surface.

| S-EPMC9301726 | biostudies-literature

6,7-Dihydro-3H-1,4-diazepino[1,2,3,4-lmn][1,10]phenanthroline-3,9(5H)-dione.

Project description:In the title compound, C(15)H(12)N(2)O(2), the seven-membered ring bearing the three methyl-ene C atoms displays a puckered conformation, with the methyl-ene C atoms deviating from the plane of the benzene ring by 0.05?(1), 0.98?(1) and 1.04?(1)?Å. The phenanthroline unit is not planar; the dihedral angles between this benzene ring and the other pyridyl rings are 9.62?(4) and 9.31?(4)°. The crystal packing is stabilized by ?-? inter-actions between two phenanthroline ring systems, forming a centrosymmetric dimer with a centroid-centroid distance of 3.656?(1)?Å.

| S-EPMC3006698 | biostudies-other

6,7-Dihydro-5H-1,4-diazepino[1,2,3,4-lmn][1,10]phenanthroline-4,8-diium tris-(thio-cyanato-κN)cuprate(I).

Project description:The title copper(I) salt, (C(15)H(14)N(2))[Cu(NCS)(3)], exists as non-inter-acting cations and trigonal-planar anions. The cation is buckled, the r.m.s. deviation of the atoms passing through the phenanthroline portion being 0.16 Å. The Cu(I) atom is displaced by 0.019 (2) Å out of the N(3) triangle. The crystal studied was a non-merohedral twin with twin domains in an approximate ratio of 55:45.

| S-EPMC2983325 | biostudies-literature

9-(2-Chloro-benz-yloxy)-6,7-dihydro-2H-benzo[c][1,2,4]triazolo[4,3-a]azepin-3(5H)-one.

Project description:In the title mol-ecule, C(18)H(16)ClN(3)O(2), the seven-membered ring adopts an envelope conformation with the flap atom deviating by 0.801 (5) Å from the mean plane formed by the remaining non-H atoms. Inter-molecular N-H⋯O hydrogen bonds link the mol-ecules into centrosymmetric dimers. The crystal packing also exhibits weak inter-molecular C-H⋯N hydrogen bonds and π-π inter-actions with a short distance of 3.734 (3) Å between the centroids of the aromatic rings of neighbouring mol-ecules.

| S-EPMC3151951 | biostudies-literature

Trimethyl-ammonium 5-(2,4-dinitro-phenyl)-2,6-dioxo-1,2,3,6-tetra-hydro-pyrimidin-4-olate 0.125-hydrate.

Project description:The asymmetric unit of the title salt C3H10N(+)·C10H5N4O7 (-)·0.125H2O [trivial name: trimethyl-ammonium 5-(2,4-dinitro-phen-yl)barbiturate 0.125-hydrate], contains two independent cations, two independent anions and a 0.25-occupancy solvent water mol-ecule. In one of the cations, the C atoms are disordered over two sets of sites with refined occupancies of 0.538?(8) and 0.462?(8). In the anions, the dihedral angles between the pyrimidine and benzene rings are 42.77?(6) and 46.55?(7)°. In the crystal, N-H?O hydrogen bonds connect anions and cations into chains along [010]. Within these chains, R 2 (2)(8) ring motifs are formed by inversion-related barbiturate anions. The H atoms of the partial occupancy water mol-ecule were not located nor included in the refinement.

| S-EPMC3629635 | biostudies-literature

2-(4-Chloro-phen-yl)-5-(3,4-dimethoxy-pheneth-yl)-6,7-dihydro-pyrazolo[1,5-a]pyrazin-4(5H)-one.

Project description:In the title compound, C(22)H(22)ClN(3)O(3), the dihedral angles between the planes of the benzene rings and the pyrazole ring are 16.05?(10) and 84.84?(10)°. The conformation of the six-membered heterocyclic ring is close to a screw-boat. The crystal packing is stabilized by weak inter-molecular C-H?O inter-actions and is also consolidated by C-H?? inter-actions.

| S-EPMC2969350 | biostudies-literature

6-Phenyl-6,7-dihydro-dibenzo[c,f][1,5]aza-bis-mocin-12(5H)-yl perchlorate.

Project description:In the title compound, [Bi(C(20)H(17)N)(ClO(4))] or C(20)H(17)BiClNO(4), the Bi(III) ion assumes a distorted ? trigonal-bipyramidal geometry, with two C atoms and the electron lone pair of the Bi atom at the equatorial positions and an amine N atom and a perchlorate O atom at the apical positions. Weak inter-molecular C-H?O hydrogen bonding is present in the crystal structure.

| S-EPMC3151844 | biostudies-other

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