Dichloroacetophenone(2,2-) / selectivity Cancer Research Results

DAP, Dichloroacetophenone(2,2-): Click to Expand ⟱
Features:
2,2-Dichloroacetophenone (DAP) is an acetophenone derivative characterized by the presence of two chlorine atoms on the aromatic ring, typically at the 2‑position relative to the carbonyl group. Its structure and properties differ significantly from compounds like dichloroacetate (DCA).
-DAP may trigger the production of reactive oxygen species (ROS) in cells.
-Increased ROS can lead to cellular damage, which may trigger apoptosis (programmed cell death) in cancer cells that are already under metabolic and oxidative stress.
-Cytotoxic effects via DNA damage.

*** Importantly, 2,2-dichloroacetophenone (DAP) is a much more potent inhibitor of PDK1(Than DCA). It is effective at concentrations in the micromolar (μM) range.
- poor aqueous solubility and lower stability of DAP limits its therapeutic application

2,2-Dichloroacetophenone — also called α,α-dichloroacetophenone, is a chlorinated aromatic ketone and experimental small-molecule inhibitor of pyruvate dehydrogenase kinase 1. It is classified as a preclinical metabolic anticancer agent and chemical research compound. DAP is structurally and pharmacologically distinct from dichloroacetate and should also be distinguished from α-chloroacetophenone, the riot-control agent commonly abbreviated CN. DAP has shown activity against acute myeloid leukemia, EGFR-mutant non-small-cell lung cancer, and prostate-cancer models, but poor aqueous solubility, limited stability, weak selectivity, and insufficient pharmacokinetic characterization restrict its translational potential.

Primary mechanisms (ranked):

  1. Inhibition of pyruvate dehydrogenase kinase 1, relieving inhibitory control of the pyruvate dehydrogenase complex and disrupting tumor glycolytic and mitochondrial energy metabolism.
  2. Destabilization of PDK1-associated survival proteins, including PI3K, Akt, ULK1, and BCL-xL, partly through altered interaction with the CBL-b ubiquitin ligase system.
  3. Induction of mitochondrial apoptosis through BAX activation, caspase-3 cleavage, PARP cleavage, and suppression of BCL-2 and BCL-xL.
  4. Suppression of PI3K/Akt/mTOR prosurvival signaling.
  5. Suppression of cytoprotective autophagy through reduced ULK1, Beclin-1, LC3-II, ATG5, and ATG7 signaling.
  6. Inhibition of proliferation, clonogenic survival, migration, and tumor growth, with reported enhancement of EGFR-tyrosine-kinase inhibitor activity and activity against some drug-resistant cancer models.

Bioavailability / PK relevance: Human pharmacokinetic data are unavailable. Free DAP has poor aqueous solubility and limited physicochemical stability, and later medicinal-chemistry studies describe weak anticancer potency and poor selectivity relative to optimized derivatives. Lactoferrin nanoparticle encapsulation improved dispersion, stability, tumor-cell targeting, and experimental antitumor efficacy, but this remains a preclinical delivery strategy.

In-vitro vs systemic exposure relevance: Most free-DAP experiments used approximately 5–100 µM, commonly around 20–40 µM. No validated human plasma concentration or clinically achievable exposure has been established. Nanoparticle-formulated DAP showed activity at lower in-vitro concentrations, including approximately 1 µM, and at 20 mg/kg in a mouse xenograft model, but these results cannot be extrapolated to human systemic exposure.

Clinical evidence status: Preclinical only. Evidence consists of cancer-cell studies and mouse xenograft experiments in acute myeloid leukemia, non-small-cell lung cancer, and prostate cancer. No completed human anticancer trial, approved therapeutic formulation, established clinical dose, or regulatory approval was identified.


Mechanistic Effects of 2,2-Dichloroacetophenone

Rank Pathway / Axis Cancer Cells Normal Cells TSF Primary Effect Notes / Interpretation
1 Pyruvate dehydrogenase kinase 1 PDK1 ↓ PDK1 may ↓ R–G Disrupts metabolic adaptation and tumor-cell survival DAP is reported to inhibit the pyruvate dehydrogenase kinase isoform PDK1 at micromolar concentrations. It is not the unrelated PDPK1 kinase of the PI3K pathway.
2 Pyruvate oxidation and glycolytic dependence PDH activity ↑; glycolytic dependence ↓; oxidative metabolism altered Metabolic effects possible R–G Reduces metabolic flexibility PDK1 inhibition is expected to relieve PDH suppression. Direct metabolic responses may vary by tumor type and formulation.
3 CBL-b and survival-protein stability CBL-b-mediated degradation ↑; PDK1, PI3K, Akt, ULK1 and BCL-xL ↓ Insufficiently characterized G Destabilizes oncogenic and anti-apoptotic proteins Mechanistic interaction data were primarily obtained in AML cells and require confirmation in additional systems.
4 Mitochondrial apoptosis BAX activation ↑; caspase-3 ↑; cleaved PARP ↑; apoptosis ↑ Possible cytotoxicity at higher concentrations G Promotes intrinsic apoptotic death Associated with loss of anti-apoptotic signaling and mitochondrial BAX oligomerization.
5 BCL-2 family survival signaling BCL-2 ↓; BCL-xL ↓ Insufficiently characterized G Lowers the apoptotic threshold BAX and BAD responses may be model-dependent; the strongest evidence concerns reduced BCL-2 and BCL-xL.
6 PI3K Akt mTOR signaling PI3K ↓; Akt ↓; mTOR signaling ↓ Potential suppression G Reduces proliferation and survival signaling This effect may be partly secondary to PDK1-associated protein destabilization rather than direct inhibition of every pathway component.
7 Autophagy machinery ULK1 ↓; Beclin-1 ↓; LC3-II ↓; ATG5 ↓; ATG7 ↓; autophagy ↓ Insufficiently characterized G Suppresses cytoprotective autophagy Autophagy inhibition was demonstrated mainly in AML cells and may enhance apoptosis under metabolic stress.
8 Proliferation and clonogenic survival Proliferation ↓; colony formation ↓; viability ↓ Lower short-term effect reported in PBMCs, but selectivity is limited G Produces cytostatic and cytotoxic effects Subsequent analogue-development work characterized unmodified DAP as weakly potent and poorly selective.
9 Migration and invasive phenotype Migration ↓; colony formation ↓ Not established G Restrains aggressive tumor behavior Reported particularly in prostate-cancer studies; evidence remains preclinical.
10 EGFR inhibitor sensitization Response to erlotinib and gefitinib ↑; apoptosis ↑ Combination toxicity not adequately defined G Enhances EGFR-targeted therapy Synergy was reported in EGFR-mutant and experimentally gefitinib-resistant NSCLC models.
11 Docetaxel resistance Docetaxel-resistant cell viability ↓ Not established G Potential chemosensitization Stronger activity was observed with lactoferrin-encapsulated DAP than with free DAP.
12 ROS and DNA damage Uncertain Uncertain R–G Not established as a primary DAP mechanism General ROS production and DNA damage should not be presented as verified core mechanisms without compound-specific experimental evidence.
13 Clinical Translation Constraint Poor solubility; limited stability; weak selectivity; formulation-dependent activity Systemic safety and therapeutic index unknown G Restricts clinical development No human PK, dose-escalation, safety, or efficacy data are available. Nanoparticle delivery improves preclinical performance but is not clinically validated.

P: 0–30 min    R: 30 min–3 hr    G: >3 hr
selectivity, selectivity: Click to Expand ⟱
Source:
Type:
The selectivity of cancer products (such as chemotherapeutic agents, targeted therapies, immunotherapies, and novel cancer drugs) refers to their ability to affect cancer cells preferentially over normal, healthy cells. High selectivity is important because it can lead to better patient outcomes by reducing side effects and minimizing damage to normal tissues.

Achieving high selectivity in cancer treatment is crucial for improving patient outcomes. It relies on pinpointing molecular differences between cancerous and normal cells, designing drugs or delivery systems that exploit these differences, and overcoming intrinsic challenges like tumor heterogeneity and resistance

Factors that affect selectivity:
1. Ability of Cancer cells to preferentially absorb a product/drug
-EPR-enhanced permeability and retention of cancer cells
-nanoparticle formations/carriers may target cancer cells over normal cells
-Liposomal formations. Also negatively/positively charged affects absorbtion

2. Product/drug effect may be different for normal vs cancer cells
- hypoxia
- transition metal content levels (iron/copper) change probability of fenton reaction.
- pH levels
- antiOxidant levels and defense levels

3. Bio-availability
Scientific Papers found: Click to Expand⟱
6685- DAP,    Anticancer effects of some novel dichloroacetophenones through the inhibition of pyruvate dehydrogenase kinase 1
- in-vitro, Lung, H1975
PDKs↓, selectivity∅, MMP↓, Apoptosis↑, lactateProd↓, ROS↑,

Showing Research Papers: 1 to 1 of 1

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 1

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress(tgid=1) ⓘ

ROS↑, 1,  

Mitochondria & Bioenergetics(tgid=3) ⓘ

MMP↓, 1,  

Core Metabolism/Glycolysis(tgid=4) ⓘ

lactateProd↓, 1,   PDKs↓, 1,  

Cell Death(tgid=5) ⓘ

Apoptosis↑, 1,  

Drug Metabolism & Resistance(tgid=21) ⓘ

selectivity∅, 1,  
Total Targets: 6

Pathway results for Effect on Normal Cells:


Total Targets: 0

Scientific Paper Hit Count for: selectivity, selectivity
Query results interpretion may depend on "conditions" listed in the research papers.
Such Conditions may include : 
  -low or high Dose
  -format for product, such as nano of lipid formations
  -different cell line effects
  -synergies with other products 
  -if effect was for normal or cancerous cells

Filter Conditions: Pro/AntiFlg:%  IllCat:%  CanType:%  Cells:%  prod#:289  Target#:1110  State#:%  Dir#:6
  wNotes=0  sortOrder:rid,rpid

 

Home Page