3.6 Toxicity estimation
In silico toxicity estimation of the drug moieties (2-DG and 2-DG
derivative) was conducted by using Toxicity Estimation Software Tool
(T.E.S.T) which predicts the key toxicity parameters (Rat acute dose
LD50, bioaccumulation factor, developmental toxicity and
Ames mutagenicity) on the basis of the chemical structure. The
fundamental principle behind such toxicological assessment is
quantitative structure activity relationship (QSAR) as generated on the
basis of OECD datasets. Computational assessment of these toxicity
parameters also aids in predicting the probable side effects of the test
compounds (Barron et al., 2012). In the present study, the tested
ligands (2-deoxy-D-glucose and 1, 3, 4,
6-Tetra-O-acetyl-2-deoxy-D-glucopyranose did not show any major signs of
toxicity or side effects as shown in Table 5 . In earlier
studies that has been carried out in animals and humans have proved that
2-deoxy-D-glucose and 1, 3, 4, 6-Tetra-O-acetyl-2-deoxy-D-glucopyranose
are safe to be administered by all routes of administration (Mohanti et
al., 1996; Singh et al., 2005; Vijayaraghavan et al., 2006). Moreover,
2-DG has already been tested for its efficacy as radio-therapeutic and
cytotoxic chemotherapeutic targeting pancreatic, breast, ovarian and
lung cancer. However, its short half life and very low bioaccumulation
factor limits the utility of 2-DG. Certain contraindications and adverse
drug reactions have also been found to be associated with higher doses
of 2-DG. These complications include fatigue, dizziness, nausea and
hypoglycemia. However, in previous studies conducted on brain tumor
patients (glioblastoma), it was observed that most of the side effects
of oral administration of 2-DG (upto doses of 250 mg /kg b.w.) are
transient and reversible (Singh et al., 2005). Additionally, the said
contraindications can be surmounted by using 2-DG derivatives as
prodrugs. Taking this into account, tetra-acetate glucopyranose
derivative of 2-DG can be used as a prodrug to improve 2-DG’s
pharmacokinetics, bioavailability and its drug-like properties (Pajak et
al., 2020).