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Chemical Structure| 1004-00-8 Chemical Structure| 1004-00-8

Structure of 1004-00-8

Chemical Structure| 1004-00-8

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Product Citations

Product Citations

Ingraham IV, Charles H ; Villanueva, Diana Polania ; Macaluso, Annamarie ; Tramuta, Annelise ; Vittori, Cecilia ; Hunter, Jean‐Jacques , et al.

Abstract: We attempt to address two key therapeutic obstacles affecting glioblastoma patients: low ability of anticancer drugs to penetrate the blood‐brain barrier (BBB), and (TMZ) resistance, by targeting mitochondrial respiration of glioblastoma cells. We designed and tested over 100 new compounds based on the chemical structure of (FF), which in its prodrug form is cytotoxic to cancer cells by causing severe impairment of mitochondrial respiration. The compounds were designed using two key predictive tools: central nervous system–multiparameter optimization (CNS‐MPO) and BBB_SCORE. These algorithms assess how effectively compounds can penetrate the BBB. We initially selected PP1 as a lead compound by testing its BBB penetration, metabolic performance, and antitumoral efficacy. PP1 accumulated in brain tumors and triggered glioblastoma cell death. However, PP1‐induced inhibition of mitochondrial respiration was followed by an immediate glycolytic response, which attenuated PP1 toxicity in a glucose‐dependent manner. To bypass this limitation, we tested two strategies: (1) the use of PP1 in combination with glycolysis inhibitors; and (2) introduction of a new compound, PP211, which inhibited mitochondrial respiration in the absence of a concomitant increase of glycolysis. Although the combination of PP1 with glycolysis inhibitors was very effective in vitro, this drug combination demonstrated elevated toxicity in mice. PP211, instead, attenuated TMZ‐resistant tumor growth and prolonged mouse survival with only minimal general animal toxicity. In summary, we developed and tested a novel mitochondria‐targeting drug candidate, PP211, which effectively crosses the BBB, overcomes TMZ resistance, and induces tumor cell death independently of glucose levels—while exhibiting minimal systemic toxicity in preclinical models. These findings support further development of PP211 for glioblastoma therapy.

Keywords: blood‐brain barrier ; drug development ; glioblastoma ; mitochondrial respiration

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Alternative Products

Product Details of [ 1004-00-8 ]

CAS No. :1004-00-8
Formula : C6H6ClNS
M.W : 159.64
SMILES Code : SC1=CC=C(Cl)C=C1N
MDL No. :MFCD00792528
InChI Key :NGIRMPARLVGMPX-UHFFFAOYSA-N
Pubchem ID :12000

Safety of [ 1004-00-8 ]

GHS Pictogram:
Signal Word:Danger
Hazard Statements:H314
Precautionary Statements:P501-P260-P264-P280-P303+P361+P353-P301+P330+P331-P363-P304+P340+P310-P305+P351+P338+P310-P405
Class:8
UN#:3259
Packing Group:

Application In Synthesis of [ 1004-00-8 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Upstream synthesis route of [ 1004-00-8 ]
  • Downstream synthetic route of [ 1004-00-8 ]

[ 1004-00-8 ] Synthesis Path-Upstream   1~1

  • 1
  • [ 1004-00-8 ]
  • [ 2941-48-2 ]
References: [1] Patent: WO2014/176258, 2014, A1, .
 

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