The development of N-functionalized 4-azapodophyllotoxins as novel anticancer agents
Date
2020-12
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
Stellenbosch : Stellenbosch University, 2020
Abstract
ENGLISH ABSTRACT: As malignant carcinomas are one of the world’s leading causes of death in terms of non-
communicable diseases, there is a strong need for the development of highly specific
antiproliferative agents. Cancer is also an ever-increasing concern in Africa, so the there is also
a need to develop anticancer agents that are easily accessible through short synthetic
strategies.
To this end, we have synthesized a small library of more than 30 novel N-functionalized 4-
azapodophyllotoxin analogues and analysed these compounds for their antiproliferative activity. The
compounds were synthesized in overall yields of 35-57% for the 4N-aryl derivatives and 18-35% for the
4N-triazolo derivatives. Multicomponent reactions (MCRs) were employed as the main method for the synthesis
of the desired scaffolds, after optimizing the procedure to afford the desired compounds from
N-functionalized naphthylamines. The N- propargyl analogues were further derivatised through “click”
chemistry with a range of different azides. The antiproliferative activity of these compounds were
determined against an oesophageal cancer cell line, WHCO1. Two of the 4N-triazolo analogues exhibited
inhibitory activities comparable to the known anticancer agent cisplatin (IC50 = 9.2 μM).
These were 11-(4-hydroxy-3,5-dimethoxyphenyl)-4-((1-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-
6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-1H-1,2,3-triazol-4-yl)methyl)-4,11- dihydrobenzo[g]furo[3,4-b]quinolin-1(3H)-one (231, IC50 = 8.8
μM) and 4-((1- ((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-1H-1,2,3-
triazol-4-yl)methyl)-11-(3,4,5-trimethoxyphenyl)-4,11-dihydrobenzo[g]furo[3,4-b]quinolin- 1(3H)-one (232, IC50 = 8.3 μM). The 4N-aryl
analogues also showed good inhibitory activity, with IC50 values ranging between 11-35 μM, with
4-(4-fluorobenzyl)-11-(4-hydroxy-3,5- dimethoxyphenyl)-4,11-dihydrobenzo[g]furo[3,4-b]quinolin-1(3H)-one (181, IC50 = 11.7
μM) and 4-benzyl-11-(3,4,5-trimethoxyphenyl)-4,11-dihydrobenzo[g]furo[3,4-b]quinolin-1(3H)-one (185, IC50 = 12.9
μM) the most potent of these compounds. The 4N-propargyl 4- azapodophyllotoxin analogues were also evaluated
for their antiproliferative activity, however, the analogues containing the podophyllotoxin and
etoposide-derived pendent rings, 174 and 176, respectively) were found to be inactive. The analogues with
the modified E-rings were, interestingly, fairly potent inhibitors, as
11-(3,5-dibromo-4-hydroxyphenyl)-4-(prop-2-yn-1-yl)- 4,11-dihydrobenzo[g]furo[3,4-b]quinolin-1(3H)-one (177,
IC50 = 2.7 μM) and 11-(5-bromo-2-
hydroxyphenyl)-4-(prop-2-yn-1-yl)-4,11-dihydrobenzo[g]furo[3,4-b]quinolin-1(3H)-one (178,
IC50 = 23.3 μM) were active against the WHCO1 cell line.
We have also undertaken in silico molecular modelling studies through the use of the Schrödinger
Maestro suite, so as to supplement our biological evaluation data and in so doing gain more
understanding into the potential active sites that these molecules target. These molecular
modelling studies did confirm literature observations that noted the importance of the 4′-hydroxyl
group on the pendent E-ring of this class of compounds. This was observed in the favourable docking
scores of active compounds such as 177, 181 and 231 against the active site of topoisomerase II.
As these compounds strongly mimic etoposide, the molecular modelling studies on the topoisomerase II crystal
structure (PDB ID: 3QX3) also gave insight as to why the 4N-triazolo- glycoside 4-azapodophyllotoxins fared better in
the antiproliferative studies than the 4N-aryl analogues, as π-π interactions between the triazole
ring and the adenosine group on the DNA fragment could be observed. The glycoside groups were
stabilized in the solvent exposed region of the active pocket.
New insights have thus been gained into the structure-activity relationships of these
compounds through the combination of biological evaluation and in silico molecular modelling.
AFRIKAANS OPSOMMING: Geen Afrikaans opsomming.
AFRIKAANS OPSOMMING: Geen Afrikaans opsomming.
Description
Thesis (PhD)--Stellenbosch University, 2020.
Keywords
Antineoplastic agents, Cancer, Chronic diseases, UCTD