Computational Study of Shuangancistrotectorine A …
199
3.4 Comparison with Previously Studied Dimeric
Naphthylisoquinoline Alkaloids
As mentioned previously, SHA, JZM and MCA (Fig. S1) are all dimeric NIQ alkaloids, which differ by the substituents in the moieties and by the fact that the two
naphthalene moieties in MCA are not identical, while they are identical in SHA and
JZM. The substituents in the moieties are as follows: two OHs, six CH 3 and six
OCH 3 in SHA; four OHs, six CH 3 and two OCH 3 in JZM; six OHs, six CH 3 and one
OCH 3 in MCA. The molecules differ also by their biological activities, as SHA and
JZM are antimalarials, whereas MCA is anti-HIV. Of the two antimalarials, JZM has
the lowest IC 50 (IC 50 = 0.0014 μM) and SHA has IC 50 = 0.052 μM.
The calculations for the three molecules were performed with the same levels
of theory and the conformational search utilised the same criteria. Input geometries
were identified considering all the possible IHB patterns (because of the known
stabilising effects of IHBs) and investigating preferred mutual orientations of the
moieties. In this way, 16 conformers were identified for SHA, 80 for JZM [4] and 22
for MCA [5]. The conformational preferences of the three molecules are influenced
by the IHB patterns (the number and type of IHBs present in a conformer) and by
the mutual orientation of the moieties [4–6]. The symmetry of the SHA and JZM
molecules yields a number of pairs of symmetric conformers on changing specific
features; such pairs mostly have comparatively high relative energy; three such pairs
were identified for SHA and 16 for JZM [4].
Three types of IHBs may be present in the three molecules: O–H···O, O–H···π and
C–H···O, with the O–H···O IHBs having the greatest stabilizing effect. The number
and positions of the IHBs is determined by the number and positions of the OH
groups: only one OH for each naphthalene moiety in SHA, whereas JZM and MCA
have OH groups also in the isoquinoline moieties. SHA and JZM may have O–H···O
IHBs only within the naphthalene moieties, whereas MCA may have O–H···O IHBs
both within each naphthalene moiety and between the two naphthalene moieties (with
the two IHBs being consecutive to each other in lower energy conformers, where they
are present simultaneously). SHA may have O–H···π IHBs only between an O–H
in the naphthalene moiety of one unit and the closest π system in the naphthalene
moiety of the other unit; JZM and MCA may have these same O–H···π IHBs and also
O–H···π IHBs between the O–H in an isoquinoline moiety and the closest π system
in the naphthalene moiety of the same unit [4, 5]. All the three molecules may have
C–H···O IHBs within an isoquinoline moiety, but SHA may also have C–H···O IHBs
between naphthalene moieties.
The bond lengths (Å) of the O–H···O IHBs within the naphthalene moieties are
the same for SHA and JZM (close to 1.73/DFT and 1.77/HF), while they are slightly
shorter in MCA (close to 1.70/DFT and 1.76/HF), likely because of the presence of
a consecutive O–H···O IHB between the two naphthalene moieties in MCA.
The isoquinoline moieties prefer to be perpendicular to the naphthalene moieties
in all the three molecules. For SHA and JZM, the naphthalene moieties also prefer
to be perpendicular to one another, which is not the case for MCA (especially for
199
3.4 Comparison with Previously Studied Dimeric
Naphthylisoquinoline Alkaloids
As mentioned previously, SHA, JZM and MCA (Fig. S1) are all dimeric NIQ alkaloids, which differ by the substituents in the moieties and by the fact that the two
naphthalene moieties in MCA are not identical, while they are identical in SHA and
JZM. The substituents in the moieties are as follows: two OHs, six CH 3 and six
OCH 3 in SHA; four OHs, six CH 3 and two OCH 3 in JZM; six OHs, six CH 3 and one
OCH 3 in MCA. The molecules differ also by their biological activities, as SHA and
JZM are antimalarials, whereas MCA is anti-HIV. Of the two antimalarials, JZM has
the lowest IC 50 (IC 50 = 0.0014 μM) and SHA has IC 50 = 0.052 μM.
The calculations for the three molecules were performed with the same levels
of theory and the conformational search utilised the same criteria. Input geometries
were identified considering all the possible IHB patterns (because of the known
stabilising effects of IHBs) and investigating preferred mutual orientations of the
moieties. In this way, 16 conformers were identified for SHA, 80 for JZM [4] and 22
for MCA [5]. The conformational preferences of the three molecules are influenced
by the IHB patterns (the number and type of IHBs present in a conformer) and by
the mutual orientation of the moieties [4–6]. The symmetry of the SHA and JZM
molecules yields a number of pairs of symmetric conformers on changing specific
features; such pairs mostly have comparatively high relative energy; three such pairs
were identified for SHA and 16 for JZM [4].
Three types of IHBs may be present in the three molecules: O–H···O, O–H···π and
C–H···O, with the O–H···O IHBs having the greatest stabilizing effect. The number
and positions of the IHBs is determined by the number and positions of the OH
groups: only one OH for each naphthalene moiety in SHA, whereas JZM and MCA
have OH groups also in the isoquinoline moieties. SHA and JZM may have O–H···O
IHBs only within the naphthalene moieties, whereas MCA may have O–H···O IHBs
both within each naphthalene moiety and between the two naphthalene moieties (with
the two IHBs being consecutive to each other in lower energy conformers, where they
are present simultaneously). SHA may have O–H···π IHBs only between an O–H
in the naphthalene moiety of one unit and the closest π system in the naphthalene
moiety of the other unit; JZM and MCA may have these same O–H···π IHBs and also
O–H···π IHBs between the O–H in an isoquinoline moiety and the closest π system
in the naphthalene moiety of the same unit [4, 5]. All the three molecules may have
C–H···O IHBs within an isoquinoline moiety, but SHA may also have C–H···O IHBs
between naphthalene moieties.
The bond lengths (Å) of the O–H···O IHBs within the naphthalene moieties are
the same for SHA and JZM (close to 1.73/DFT and 1.77/HF), while they are slightly
shorter in MCA (close to 1.70/DFT and 1.76/HF), likely because of the presence of
a consecutive O–H···O IHB between the two naphthalene moieties in MCA.
The isoquinoline moieties prefer to be perpendicular to the naphthalene moieties
in all the three molecules. For SHA and JZM, the naphthalene moieties also prefer
to be perpendicular to one another, which is not the case for MCA (especially for