Recent Advances in the Chemistry and Pharmacology of Cryptolepine
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gastric, and NCI-H460 non-small cell lung), plus HL7702 normal human hepatocytes [57]. One compound, 8-fluoro-10-(N-3-dimethylaminopropyl)amino-11Hindeno[1,2-b]quinoline (52), demonstrated the best cancer cell line-specific cytotoxicity, and was selected for further investigation. It was seen to bind strongly
to G-quadruplex sequences of DNA, including c-kit, as well as to intercalate into
supercoiled DNA, resulting in significant double-strand DNA breaks. Additionally,
treatment with 52 was observed to cause S/G2 cell cycle arrest, and induce apoptosis, with up-regulation of the pro-apoptotic proteins Bak, Bax, and Bim, and downregulation of the anti-apoptotic proteins Bcl-2 and Bcl-xL. In addition, activation of
the apoptosis effector caspase 3/9 occurred.
Enhanced cytotoxicity was found in a study where 11-aminoalkyl and 11-halo
substitutions were made at the C-11 position of 1 [68]. While these compounds
demonstrated topoisomerase II inhibitory activity, their results suggested that direct
intercalation with duplex-DNA and cell permeability are important factors in potency.
Induction of autophagy has also been described as a mechanism for antineoplastic
activity for analogs of 1 [69]. Following treatment of the nasopharyngeal human
cancer cell lines CNE1, CNE2, and HONE1 with N
-(10H-indolo[3,2-b]quinolin11-yl)-N,N-dimethyl-propane-1,3-diamine (53), it was seen that at both the gene and
protein level, several markers of autophagy were induced. These included BNIP3,
LC3, and FOXO3a.
9.3 Antineoplastic Agents: In Vivo Studies
While in vitro studies are useful for elucidating the mechanism of action of 1 and
its analogs, these studies do not give much indication as to the bioavailability of the
compounds and off-target toxicities when applied to a body system. For an understanding of this, in vivo studies are required, and there are three recent studies that
report on the in vivo administration of 1 [56], and its analogs [57, 58], which all
demonstrate promising activity. In a study by Pal et al. from 2017, 1 was administered
intraperitoneally, three times weekly for 24 days (10 mg/kg/dose) to immunodeficient
mice bearing subcutaneously implanted A357 human melanoma cell line xenografts
[56]. A significant (p < 0.001) inhibition of tumor growth was seen for the treated
group compared to the control, with no evidence of toxicity to the mice using this
regimen. Furthermore, studies of the tumor tissue post-mortem using biomarkers
for the regulation of mitochondrial dynamics and biogenesis demonstrated that 1
disrupted these processes [56]. In work by Yuan et al. from 2019, 52 was administered intraperitoneally every 2 days for 14 days at either 6 or 12 mg/kg/dose to
immunodeficient mice bearing subcutaneously implanted MGC-803 human gastric
cancer cell line xenografts. Significant inhibition in tumor growth was seen for both
doses (p < 0.05 for the 6 mg/kg/dose, and p < 0.01 for the 12 mg/kg/dose), with the
higher dose having a similar effect as the control standard agent camptothecin [57].
Encouragingly, there was no evidence of toxicity with this test compound.
195
gastric, and NCI-H460 non-small cell lung), plus HL7702 normal human hepatocytes [57]. One compound, 8-fluoro-10-(N-3-dimethylaminopropyl)amino-11Hindeno[1,2-b]quinoline (52), demonstrated the best cancer cell line-specific cytotoxicity, and was selected for further investigation. It was seen to bind strongly
to G-quadruplex sequences of DNA, including c-kit, as well as to intercalate into
supercoiled DNA, resulting in significant double-strand DNA breaks. Additionally,
treatment with 52 was observed to cause S/G2 cell cycle arrest, and induce apoptosis, with up-regulation of the pro-apoptotic proteins Bak, Bax, and Bim, and downregulation of the anti-apoptotic proteins Bcl-2 and Bcl-xL. In addition, activation of
the apoptosis effector caspase 3/9 occurred.
Enhanced cytotoxicity was found in a study where 11-aminoalkyl and 11-halo
substitutions were made at the C-11 position of 1 [68]. While these compounds
demonstrated topoisomerase II inhibitory activity, their results suggested that direct
intercalation with duplex-DNA and cell permeability are important factors in potency.
Induction of autophagy has also been described as a mechanism for antineoplastic
activity for analogs of 1 [69]. Following treatment of the nasopharyngeal human
cancer cell lines CNE1, CNE2, and HONE1 with N
-(10H-indolo[3,2-b]quinolin11-yl)-N,N-dimethyl-propane-1,3-diamine (53), it was seen that at both the gene and
protein level, several markers of autophagy were induced. These included BNIP3,
LC3, and FOXO3a.
9.3 Antineoplastic Agents: In Vivo Studies
While in vitro studies are useful for elucidating the mechanism of action of 1 and
its analogs, these studies do not give much indication as to the bioavailability of the
compounds and off-target toxicities when applied to a body system. For an understanding of this, in vivo studies are required, and there are three recent studies that
report on the in vivo administration of 1 [56], and its analogs [57, 58], which all
demonstrate promising activity. In a study by Pal et al. from 2017, 1 was administered
intraperitoneally, three times weekly for 24 days (10 mg/kg/dose) to immunodeficient
mice bearing subcutaneously implanted A357 human melanoma cell line xenografts
[56]. A significant (p < 0.001) inhibition of tumor growth was seen for the treated
group compared to the control, with no evidence of toxicity to the mice using this
regimen. Furthermore, studies of the tumor tissue post-mortem using biomarkers
for the regulation of mitochondrial dynamics and biogenesis demonstrated that 1
disrupted these processes [56]. In work by Yuan et al. from 2019, 52 was administered intraperitoneally every 2 days for 14 days at either 6 or 12 mg/kg/dose to
immunodeficient mice bearing subcutaneously implanted MGC-803 human gastric
cancer cell line xenografts. Significant inhibition in tumor growth was seen for both
doses (p < 0.05 for the 6 mg/kg/dose, and p < 0.01 for the 12 mg/kg/dose), with the
higher dose having a similar effect as the control standard agent camptothecin [57].
Encouragingly, there was no evidence of toxicity with this test compound.