본문 바로가기
HOME> 논문 > 논문 검색상세

논문 상세정보

European journal of medicinal chemistry v.143, 2018년, pp.244 - 258   SCI SCIE
본 등재정보는 저널의 등재정보를 참고하여 보여주는 베타서비스로 정확한 논문의 등재여부는 등재기관에 확인하시기 바랍니다.

Targeting tubulin polymerization by novel 7-aryl-pyrroloquinolinones: Synthesis, biological activity and SARs

Bortolozzi, Roberta (Department of Woman's and Child's Health, University of Padova, Laboratory of Oncohematology, 35128 Padova, Italy ) ; Mattiuzzo, Elena (Department of Woman's and Child's Health, University of Padova, Laboratory of Oncohematology, 35128 Padova, Italy ) ; Dal Pra, Matteo (Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy ) ; Sturlese, Mattia (Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy ) ; Moro, Stefano (Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy ) ; Hamel, Ernest (Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA ) ; Carta, Davide (Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy ) ; Viola, Giampietro (Department of Woman's and Child's Health, University of Padova, Laboratory of Oncohematology, 35128 Padova, I ) ; Ferlin, Maria Grazia ;
  • 초록  

    Abstract Earlier studies had confirmed that the 7-phenylpyrroloquinolinone (7-PPyQ) nucleus was an important scaffold for new chemotherapeutic drugs targeting microtubules. For wide-ranging SARs, a series of derivatives were synthesized through a robust procedure. For comparison with the reference 3-ethyl-7-PPyQ 31 , the angular geometry and substituents at the 3 and 7 positions were varied to explore interactions inside the colchicine site of tubulin. Of the new compounds synthesized, potent cytotoxicity (low and sub-nanomolar GI 50 values) was observed with 21 and 24 , both more potent than 31, in both leukemic and solid tumor cell lines. Neither compound 21 nor 24 induced significant cell death in normal human lymphocytes, suggesting that the compounds may be selectively active against cancer cells. In particular, 24 was a potent inducer of apoptosis in the A549 and HeLa cell lines. With both compounds, induction of apoptosis was associated with dissipation of the mitochondrial transmembrane potential and production of reactive oxygen species, indicating that cells treated with the compounds followed the intrinsic pathway of apoptosis. Moreover, immunoblot analysis revealed that compound 24 even at 50 nM reduced the expression of anti-apoptotic proteins such as Bcl-2 and Mcl-1. Finally, molecular docking studies of the newly synthesized compounds demonstrate that active pyrroloquinolinone derivatives strongly bind in the colchicine site of β-tubulin. Highlights A small library of 7-pyrrolo[3,2- f ]quinolinones was synthesized. One of the most active compound 24 showed GI 50 s ranging from 0.2 to 123 nM. Compound 24 did not induce significant cell death in normal human lymphocytes. Compound 24 overcomes multi-drug resistance. Compounds, 24 strongly inhibited tubulin assembly assay with an IC 50 of 0.84 μM. Graphical abstract [DISPLAY OMISSION]


  • 주제어

    Microtubules .   Phenylpyrroloquinolinone .   Tubulin .   Apoptosis .   Molecular docking .   Structure-activity relationships.  

 활용도 분석

  • 상세보기

    amChart 영역
  • 원문보기

    amChart 영역

원문보기

무료다운로드
  • 원문이 없습니다.

유료 다운로드의 경우 해당 사이트의 정책에 따라 신규 회원가입, 로그인, 유료 구매 등이 필요할 수 있습니다. 해당 사이트에서 발생하는 귀하의 모든 정보활동은 NDSL의 서비스 정책과 무관합니다.

원문복사신청을 하시면, 일부 해외 인쇄학술지의 경우 외국학술지지원센터(FRIC)에서
무료 원문복사 서비스를 제공합니다.

NDSL에서는 해당 원문을 복사서비스하고 있습니다. 위의 원문복사신청 또는 장바구니 담기를 통하여 원문복사서비스 이용이 가능합니다.

이 논문과 함께 출판된 논문 + 더보기