WO2015080681A1 - Composés de phénothiazine-pyrimidine-2,4(1h, 3h)-dione pour le traitement du cancer - Google Patents

Composés de phénothiazine-pyrimidine-2,4(1h, 3h)-dione pour le traitement du cancer Download PDF

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Publication number
WO2015080681A1
WO2015080681A1 PCT/TR2014/000439 TR2014000439W WO2015080681A1 WO 2015080681 A1 WO2015080681 A1 WO 2015080681A1 TR 2014000439 W TR2014000439 W TR 2014000439W WO 2015080681 A1 WO2015080681 A1 WO 2015080681A1
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WO
WIPO (PCT)
Prior art keywords
thioridazine
cancer
phenothiazine
pyrimidine
dopamine receptor
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PCT/TR2014/000439
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English (en)
Inventor
Ahmet Cenk ANDAC
Haci Ramazan YILMAZ
Nadir KOÇAK
Mustafa KISA
Gozde YALCIN
Original Assignee
Andac Ahmet Cenk
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Publication date
Application filed by Andac Ahmet Cenk filed Critical Andac Ahmet Cenk
Publication of WO2015080681A1 publication Critical patent/WO2015080681A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to the design and synthesis of novel thioridazine derivatives that are thought to have anticancer effects greater than thioridazine.
  • Tuynder et al. reported in 2004 that thioridazine apoptosized or differentiated human erythroleukemia and tamoxifen-resistant mammary cancer cells through down-regulation of translationally controlled tumor protein (TCTP).
  • TCTP translationally controlled tumor protein
  • Tuynder et al. proposed that the down-regulation of TCTP could relate to the antagonistic effects of thioridazine on dopamine receptors expressed by cancer cells.
  • This invention relates to novel compounds derived from thioridazine that are designed to exert strong anticancer effect.
  • the main objective of the study is to synthesize novel phenothiazine derivatives, that are predicted to have greater affinity and specificity towards the D2 dopaminergic receptor with less side effects than thioridazine, to determine their anticancer effects on cancer and cancer stem cell lines.
  • thioridazine a phenothiazine pharmacophore derivative
  • the therapeutic index of thioridazine is quite low. Indeed, its use has been banned in many countries due to agranulocytosis, arythmia, and sudden death cases reported in the past.
  • Thioridazine not only binds to dopamine receptors but also muscarinic, serotonin, and a-adrenergic receptors, unavoidably giving rise to side effects. Despite its side effects, thioridazine has been recently placed into reconsideration for preclinical studies in AML stem cell line.
  • the aim of our invention is to synthesize novel derivatives of thioridazine, namely 1-(2-methylthio-10H-phenothiazine-10-yl-propyl)- pyrimidine-2,4(1H,3/-/)-dione ( Figure 3) and 3-(2-methylthio-10H-phenothiazine- 10-yl-propyl)pyrimidine-2,4(1/-/,3H)-dione (Figure 4), which were designed to more strongly bind D2 dopamine receptor and yet with less side effects as compared to thioridazine, and determine their anticancer effects on cancer and cancer stem cell lines.
  • phenothiazine derivatives in literature.
  • the proposed novel compounds may be used in the treatment of cancer with lesser cytotoxic side effects at therapeutic doses due possibly to a greater therapeutic index as they are expected to selectively bind the D2 dopamine receptor with higher affinity.
  • the proposed compounds are thought to exert their effects on MCF-7 (ER+/PR+) human mammary ductal adenocarcinoma and MCF-7 (ER+/PR+;CD44+/CD24-) human mammary cancer stem celMines.
  • the apoptotic and differentiation pathways triggered by the proposed compounds will be determined by monitoring p53 and Oct-4 mRNA gene expressions using Quantitatif Real Time PCR.
  • our primary objective is to prove the anticancer effect of the proposed compounds on cancer stem lines. Having a great sequence homology between human D2 and human D3 dopamine receptors (78%) makes it difficult to develop more specific novel drugs for these receptors.
  • the compounds proposed may also be used as neuroleptic agents for illumination of physiological and behavioral moods if they proove to be highly D2 dopamine receptor specific.
  • Platania et al. were able to compare 3 ns explicit solvent molecular dynamics structures of human D2L and D3 dopamine receptors embedded in POPC (palmitoyl-oleoyl phosphatidyl choline) bilayer membrane and found that the binding site of D21. is greater than, that of D3 dopamine receptor.
  • Platania et al. proposed that molecules bulkier than eticlopride, such as phenothiazine derivatives, may have a greater affinity towards D21. dopamine receptor, a finding that should be taken into consideration for drug development.
  • D3 and D2L dopamine receptors share 73.4% aminoacid sequence, homology.
  • the aminoacid sequence of human D2L dopamine receptor is available at Protein Blast and Swiss-Prot Data Bank.
  • DSC Discovery Studio Client
  • the binding site of the D3 dopamine receptor is hydrophobic.
  • the D2L dopamine receptor possesses a VAL180 to GLU181 mutation with a carboxyl (COO ) tail that is ought to form H-bonding interaction with a suitable ligand.
  • This is thought to be a unique property of the D2L receptor that is crucial in the developent of novel and specific antagonists/inverse agonists, in that, chemical addition of a H-bond donor, such as a N-H group, to the alkyl bridge of phenothiazine is thought to enable the novel phenothiazine derivative to form a H-bond with GLU 181 -COO * .
  • disulfide brigdes available in the E3 and TM3-E3 regions of the D2L dopamine receptors. Particularly, the disulfide bond in the TM3-E2 regions makes a contribution to stability of the D2L dopamine receptor, while the other disulfide bond in the E3 region contributes to a sharp U-turn in the E3 region.
  • the first objective of this project is to synthesize, purify and characterize the compounds 1-(2-methylthio-10H-phenothiazine-10-yl-propyl)- pyrimidine-2,4(1 H,3H)-dione and 3-(2-methylthio-10H-phenothiazine-10-yl- propyl)pyrimidine-2,4(1H,3H)-dione.
  • the second objective of the project is to determine the anticancer activities of the synthesized compounds on MCF-7 (ER+/PR+) human mammary ductal adenocarcinoma and MCF-7 (ER+/PR+;CD44+/CD24-) human mammary cancer stem cell lines.

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention concerne de nouveaux dérivés de thioridazine qui auront des effets plus forts contre le cancer. L'objectif de l'étude est de synthétiser de nouveaux dérivés de thioridazine, qui devraient être de meilleurs antagonistes/agonistes inverses du récepteur dopaminergique D2, ayant moins d'effets secondaires comparativement à la thioridazine, et de tester leurs effets anticancéreux sur le cancer et sur des lignées de cellules souches cancéreuses afin de déterminer leurs potentiels en termes d'utilisation dans le traitement du cancer.
PCT/TR2014/000439 2013-11-29 2014-11-19 Composés de phénothiazine-pyrimidine-2,4(1h, 3h)-dione pour le traitement du cancer WO2015080681A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR201313919 2013-11-29
TR2013/13919 2013-11-29

Publications (1)

Publication Number Publication Date
WO2015080681A1 true WO2015080681A1 (fr) 2015-06-04

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PCT/TR2014/000439 WO2015080681A1 (fr) 2013-11-29 2014-11-19 Composés de phénothiazine-pyrimidine-2,4(1h, 3h)-dione pour le traitement du cancer

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WO (1) WO2015080681A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005027842A2 (fr) * 2003-09-18 2005-03-31 Combinatorx, Incorporated Associations de medicaments destinees au traitement de tumeurs
US20130261074A1 (en) * 2012-03-28 2013-10-03 Mickie Bhatia Combination therapy for the treatment of cancer

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005027842A2 (fr) * 2003-09-18 2005-03-31 Combinatorx, Incorporated Associations de medicaments destinees au traitement de tumeurs
US20130261074A1 (en) * 2012-03-28 2013-10-03 Mickie Bhatia Combination therapy for the treatment of cancer

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MARCEL TUYNDER ET AL: "Translationally controlled tumor protein is a target of tumor reversion", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, NATIONAL ACADEMY OF SCIENCES, US, vol. 101, no. 43, 26 October 2004 (2004-10-26), pages 15364 - 15369, XP002649549, ISSN: 0027-8424, [retrieved on 20041015], DOI: 10.1073/PNAS.0406776101 *

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