| dc.description.abstract | The thesis entitled “The Crystal and Molecular Structures of Some Molecules of Biological Interest and Moderately Strained Organic Molecules” consists of two parts: Part One deals with biologically important molecules and Part Two with moderately strained organic molecules.
Part One
The molecules of biological interest under consideration in this thesis are three derivatives of testosterone and a potent tricyclic antidepressant drug. Testosterone (I) (Fig. 1), a principal hormone of the testes, is a powerful androgenic and anabolic agent and is responsible for the male sex characteristics. A systematic investigation of some of the derivatives of testosterone (Fig. 1) was undertaken in this laboratory to gain some knowledge about the structural and conformational features essential for the androgenic and anabolic receptor binding.
19?nor?testosterone (II) (Fig. 1), identical to testosterone except for the absence of the methyl group at C(19), retains the anabolic activity (retention of nitrogen in the body) of (I) but the androgenic activity (responsible for the male sex characteristics) is relatively weak. The crystal structure of (II) crystallized from hexane has already been reported (Precigoux, Busetta, Oourseille, and Hospital, 1975) in the monoclinic space group
P21
P2
1
?
with
a=10.045(5)
a=10.045(5),
b=10.761(5)
b=10.761(5),
c=14.497(6) A?
c=14.497(6)
A
?
, and
?=89.36(10)?
?=89.36(10)
?
with
Z=4
Z=4. These authors found atoms O(1) and C(2) in ring A to be disordered.
The present author has obtained another modification of (II) from ethanol crystallizing in the same space group with unit?cell parameters
a=9.755(2)
a=9.755(2),
b=11.467(3)
b=11.467(3),
c=14.196(3) A?
c=14.196(3)
A
?
, and
?=101.07(2)?
?=101.07(2)
?
with
Z=4
Z=4, and the results are presented in Chapter II. The structure has been solved by direct methods and refined to an
R
R value of 0.060 (
Rw=0.065
R
w
?
=0.065) for 2158 significant reflections measured on a four?circle CAD?4 diffractometer. There was no evidence for any disorder of atoms in the ring A as observed in the modification investigated by Precigoux et al. (1975). However, ring A was found to be more flexible than the other rings. The molecules with all trans junctions are essentially flat as observed in (I) (Roberts, Petterson, Sheldrick, Isaacs, and Keimard, 1973). The possible reasons for the difference in the biological activities between molecules (I) and (II) are discussed.
8?Iso?testosterone (III) (Fig. 1), an isomer of testosterone with the reversal of configuration at the C(8) position, has only about 40?% activity of testosterone. The crystal structure of (III) has been determined earlier in our laboratory (Chakrabarti, Banerjee, and Venkatesan, 1981). If the configurations are reversed at positions C(8) as well as C(10), the molecules 8?iso?10?iso?testosterone (V) and 8?iso?10?iso?19?nor?testosterone (VI) (Fig. 1) do not show any significant androgenic or anabolic activity. Chapter II reports the results of X?ray studies on (V) and (VI). 8?Iso?19?nor?testosterone (IV) was available in very little quantity and could not be crystallized. The crystals of (V) are hexagonal, space group
P61
P6
1
?
with
a=20.224(4)
a=20.224(4),
c=7.358(5) A?
c=7.358(5)
A
?
,
?=120?
?=120
?
, and
Z=6
Z=6. The crystals of (VI) belong to the monoclinic space group
P21
P2
1
?
with
a=7.419(3)
a=7.419(3),
b=17.852(5)
b=17.852(5),
c=6.232(4) A?
c=6.232(4)
A
?
, and
?=112.41(5)?
?=112.41(5)
?
with
Z=2
Z=2. Both (V) and (VI) have been solved by direct methods and refined to
R
R indices of 0.085 (
Rw=0.079
R
w
?
=0.079) for 823 significant reflections and 0.056 (
Rw=0.051
R
w
?
=0.051) for 921 significant reflections respectively. Both molecules are folded considerably as the B/C ring junction is cis in contrast to the trans junction in (I) and (II). On the basis of the X?ray studies of these isomers, topological requirements for the androgenic receptor binding are discussed.
The molecular structure and conformation of a tricyclic antidepressant, nitroxazepine hydrochloride (Sintamil·HCl), is presented in Chapter III. The drug molecule (I) (Fig. 2) crystallizes in the orthorhombic space group
Pn21a
Pn2
1
?
a with
a=7.710(4)
a=7.710(4),
b=11.455(3)
b=11.455(3),
c=21.199(3) A?
c=21.199(3)
A
?
, and
Z=4
Z=4. The structure has been solved in the space group
Pn21a
Pn2
1
?
a by direct methods and refined to an
R
R value of 0.045 for 1470 observed reflections. The tricyclic ring system is folded and the dihedral angle between the benzene rings is 125.0°. The conformation of the side chain is similar to one of the conformations of imipramine·HCl, a well?known antidepressant, with the side chain possessing a folded conformation. Some observations on the conformational features essential for the antidepressant activity of tricyclic drugs are discussed | |
