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Biomedical subjects

D Ranganathan

Publications and source records attributed to D Ranganathan.

At least 19 recordsLinked to original sources

Acute and subacute toxicity studies of Aegle marmelos Corr., an Indian medicinal plant.

This study was designed to elucidate the toxicity of the widely used plant Aegle marmelos in rats. We have taken total alcoholic, total aqueous, whole aqueous and methanolic extracts isolated from the leaves of A. marmelos and studied their toxic effects. Acute, subacute and LD(50) values were determined in experimental rats. The dead animals were obtained from primary screening studies, LD(50) value determination experiments and acute studies subjected to postmortem studies. The external appearance of the dead animals, the appearance of the viscera, heart, lungs, stomach, intestine, liver, kidney, spleen and brain were carefully noted and any apparent and significant features or differences from the norm were recorded. Following the chronic administration of A. marmelos for 14 days, the vital organs such as heart, liver, kidney, testis, spleen and brain were carefully evaluated by histopathological studies and any apparent and significant changes or differences from the norm were studied. From the acute administration of A. marmelos, the LD(50) values were determined using graphical method. The hearts stopped in systolic stand-still in the acute experiments. There were no remarkable changes noticed in the histopathological studies after 50 mg/kg body wt of the extracts of A. marmelos when administered intraperitoneally for 14 days successively. Pathologically, neither gross abnormalities nor histopathological changes were observed. After calculation of LD(50) values using graphical methods, we found a broad therapeutic window and a high therapeutic index value for A. marmelos extracts. Intraperitoneal administration of the extracts of the leaves of A. marmelos at doses of 50, 70, 90 and 100 mg/kg body wt for 14 consecutive days to male and female Wistar rats did not induce any short-term toxicity. Collectively, these data demonstrate that the extracts of the leaves of A. marmelos have a high margin of drug safety.

Aegle↗

An asymmetric conformation of 1,3,5-benzene tricarbonyl [Aib4OMe]3.

Molecules of 1,3,5-benzene tricarbonyl [Aib(4)OMe](3) do not possess any internal symmetry, neither exact nor approximate, in the crystalline state. The Aib(4)OMe moieties each form a 3(10)-helix with an appropriate pair of hydrogen bonds but the sense of rotation is right-handed for two of the helices and left-handed for the third one. The helices are not evenly positioned around the benzene ring, and their helix axes are inclined toward one side of the plane of the benzene ring, giving the molecule the shape of a shallow bowl with an irregular periphery. The molecules are largely surrounded by water and dimethyl sulfoxide (DMSO) solvent molecules that form hydrogen bonds with the CO and NH moieties that protrude from the surfaces of the peptide molecule. The space group is Cc with a = 23.618(4) A, b = 19.708(6) A, c = 17.939(7) A and beta = 100.09(3) degrees.

Hydrogen Bonding↗

Self-assembling, cystine-derived, fused nanotubes based on spirane architecture: design, synthesis, and crystal structure of cystinospiranes.

A novel family of cystine-based spirobicyclic peptides (cystinospiranes) has been synthesized by a single-step procedure involving condensation of pentaerythritol-derived tetrachloride with either the simple L-cystine dimethyl ester or its C,C'-extended bispeptides leading to a variety of 19-membered spirobicyclic peptides or its N,N'-extended bispeptides affording the ring-expanded 25-membered cystinospiranes. The design is flexible with respect to the ring size that can be adjusted depending upon the length of the N,N'-extended cystine bispeptide, and the choice of an amino acid, as illustrated here with the preparation of a large number of cystinospiranes containing a wide variety of amino acids. X-ray crystal structure of the parent spirane (5a) revealed nanotube formation by vertical stacking of relatively flat spirobicyclic molecules through contiguous NH- - -O==C hydrogen bonding. The fused pair of parallel nanotubes is open-ended, hollow, and extends to infinity. Crystallographic parameters are the following: C(33)H(52)N(4)O(16)S(4), space group C2, a = 42.181(3) A, b = 5.1165(7) A, c = 11.8687(9) A, beta = 106.23(1) degrees.

Crystallization↗

Designer hybrid cyclopeptides for membrane ion transport and tubular structures.

The incorporation of chosen, non-amino acids into cyclopeptides is a promising approach to designs capable of performing specific tasks. While such hybrid cyclopeptides are common in the microbial world, there is hardly any effort by synthetic organic chemists to explore such designs for creating architecturally beautiful and functionally useful macrocyclic hybrid peptides. This Account, mainly reviewing the author's own work, presents a simple design strategy enabling the crafting of a large variety of hybrid cyclopeptides and leading to the identification of excellent membrane ion carriers, units that self-assemble into tubular structures, and systems for specific guest recognition.

Cell Membrane↗

Design, synthesis, and crystal structure of self-assembling norbornene (NBE)-supported two-helix bundles: a unique example of Janus helicity in the solid-state structure of NBE(Aib(5))(2).

Norbornene-supported bis-helical peptides with the general structure NBE(Aib(n) )(2) (NBE: 2,3-trans-norbornene dicarbonyl unit; Aib: alpha,alpha'-dimethyl glycine unit; n = 4,5) have been synthesized and examined for self-assembly preferences in the solid state. An x-ray study has revealed a phenomenon of Janus helicity in the solid state structure of NBE(Aib(5))(2). The lower homologue NBE(Aib(4))(2), however, shows an identical screw sense for both the helical arms. The difference in the handedness of left and right arms is reflected in the self-assembly patterns. Thus, while the NBE(Aib(4))(2) molecule self-assembles to form an infinite hydrogen-bonded superhelical ladder, the Janus molecule NBE(Aib(5))(2) crystallizes as individual units surrounded by water molecules. The structures of Z-Aib(4)-OMe and Z-Aib(5)-OMe are also presented to compare their conformations with the helical arms of the title compound and also to the already known structures of other X-Aib(n) -Y compounds. The helices in all the molecules are the 3(10)-type.

Crystallography, X-Ray↗

Design and synthesis of AB(3)-type (A = 1,3,5-benzenetricarbonyl unit; B = Glu diOME or Glu(7) octa OMe) peptide dendrimers: crystal structure of the first generation.

The first generation molecule of glutamic acid-based dendrons on a 1, 3,5-benzenetricarbonyl core leads to a cylindrical assembly as demonstrated by single crystal x-ray diffraction. The benzene pi-pi stack (A) is stabilized by vertical NH...O===C hydrogen bonding with each subunit participating in three intermolecular hydrogen bonds related by three-fold rotation symmetry.

Benzene Derivatives↗

Double-helical cyclic peptides: design, synthesis, and crystal structure of figure-eight mirror-image conformers of adamantane-constrained cystine-containing cyclic peptide cyclo (Adm-Cyst)(3).

A large number of macrocycles containing alternating repeats of cystine diOMe(-NH-CH(CO(2)Me)-CH(2)-S-)(2) and either a conformationally rigid aromatic/alicyclic moiety or a flexible polymethylene unit (X) in the cyclic backbone with ring size varying from 13- to 78-membered have been examined by spectral ((1)H NMR, FT-IR, CD) and X-ray crystallography studies for unusual conformational preferences. While (1)H NMR measurements indicated a turnlike conformation for all macrocycles, stabilized by intramolecular NH.CO hydrogen bonding, as also supported by FT-IR spectra in chloroform, convincing proof for beta-turn structures was provided by circular dichroism studies. Single-crystal X-ray studies on 39-membered cyclo (Adm-L-Cyst)(3) revealed a double-helical fold (figure-eight motif) for the macrocycle. Only a right-handed double helix was seen in the macrocycle constructed from L-cystine. The mirror-image macrocycle made up of D-cystine units exhibited a double helix with exactly the opposite screw sense, as expected. The enantiomeric figure-eights were stabilized by two intramolecular NH. CO hydrogen bonds and exhibited identical (1) H NMR and FT-IR spectra. The CD spectra of both isomers had a mirror-image relationship. The present results have clearly brought out the importance of cystine residues in inducing turn conformation that may be an important deciding factor for the adoption of topologically important structures by macrocycles containing multiple S-S linkages.

Crystallography, X-Ray↗

Norbornene-constrained cyclic peptides with hairpin architecture: design, synthesis, conformation, and membrane ion transport.

A novel family of hairpin cyclic peptides has been designed on the basis of the use of norbornene units as the bridging ligands. The design is flexible with respect to the choice of an amino acid, the ring size, and the nature of the second bridging ligand as illustrated here with the preparation of a large number of norborneno cyclic peptides containing a variety of amino acids in ring sizes varying from 12- to 29-membered, with the choice of the second bridging ligand being a rigid norbornene (11, 13a,b), an adamantane unit (7a,b and 8), or a flexible cystine residue (4a,b and 10). The presence of built-in handles (as protected COOH groups) permits the attachment of a variety of subunits as shown here with the ligation of Leu-Leu, Val-Val, or Aib-Aib pendants in 4b, 7b, and 13b, respectively. This novel class of constrained cyclic peptides are demonstrated to adopt beta-sheet- or hairpin-like conformation as shown by (1)H NMR and CD spectra. Membrane ion-transport studies have shown that the norborneno cyclic peptides 4b and 7b containing Leu-Leu or Val-Val pendants symmetrically placed on the exterior of the ring show high efficiency and selectivity in the transport of specifically monovalent cations. This property can be attributed to the hairpin-like architecture induced by the norbornene unit since the bis-adamantano peptide 15 containing two pairs of Leu-Leu pendants on the exterior is able to transport both monovalent (Na(+), K(+)) and divalent (Mg(2+)/Ca(2+)) cations.

Circular Dichroism↗

Racial differences in respiratory-related neonatal mortality among very low birth weight infants.

OBJECTIVE: To examine racial differences in the secular trends in respiratory-related neonatal mortality among very low birth weight (VLBW) infants in the United States, temporally associated with surfactant availability. DESIGN: Comparison of time trends in African American and non-Hispanic white (NHW) VLBW infants of cause-specific neonatal mortality and neonatal and infant mortality for 2 consecutive 3-year periods. RESULTS: From 1985 to 1988 there was no racial difference in the rate of decline of each mortality outcome. From 1988 to 1991 rates of decline in neonatal mortality caused by respiratory distress syndrome and by all respiratory causes were significantly greater for NHWs compared with African Americans. However, the rate of decline in nonrespiratory neonatal mortality was similar for African Americans and NHWs. Compared with African American VLBW infants, NHWs had a greater rate of decline in both neonatal (31% vs 20%; P <.01) and infant mortality (32% vs 21%; P <.01) during this period. CONCLUSIONS: Between 1988 and 1991, declines in neonatal mortality risks caused by respiratory distress syndrome and all respiratory causes were greater for NHW infants than for African American VLBW infants. The decline in nonrespiratory mortality risk showed no racial differences. These findings suggest possible racial disparities in timely access or racial differences in the efficacy of respiratory treatments for VLBW infants.

Black People↗

Channel-forming, self-assembling, bishelical amphiphilic peptides: design, synthesis and crystal structure of Py(Aibn)2, n=2,3,4.

The design, synthesis, characterization and self-assembling properties of a new class of amphiphilic peptides, constructed from a bifunctional polar core attached to totally hydrophobic arms, are presented. The first series of this class, represented by the general structure Py(Aibn)2 (Py=2,6-pyridine dicarbonyl unit; Aib=alpha, alpha'-dimethyl glycine; n=1-4), is prepared in a single step by the condensation of commercially available 2,6-pyridine dicarbonyl dichloride with the methyl ester of homo oligoAib peptide (Aibn-OMe) in the presence of triethyl amine. 1H NMR VT and ROESY studies indicated the presence of a common structural feature of 2-fold symmetry and an NH...N hydrogen bond for all the members. Whereas the Aib3 segment in Py(Aib3)2 showed only the onset of a 3(10)-helical structure, the presence of a well-formed 3(10)-helix in both Aib4 arms of Py(Aib4)2 was evident in the 1H NMR of the bispeptide. X-ray crystallographic studies have shown that in the solid state, whereas Py(Aib2)2 molecules organize into a sheet-like structure and Py(Aib3)2 molecules form a double-stranded string assembly, the tetra Aib bispeptide, Py(Aib4)2, is organized to form a tetrameric assembly which in turn extends into a continuous channel-like structure. The channel is totally hydrophobic in the interior and can selectively encapsulate lipophilic ester (CH3COOR, R=C2H5, C5H11) molecules, as shown by the crystal structures of the encapsulating channel. The crystal structure parameters are: 1b, Py(Aib2)2, C25H37N5O8, sp. gr. P2(1)2(1)2(1), a=9.170(1) A, b=16.215(2) A, c=20.091(3) A, R=4.80; 1c, Py(Aib3)2, C33H51N7O10H2O, sp. gr. P1, a=11.040(1) A, b=12.367(1) A, c=16.959(1) A, alpha =102.41 degrees, beta =97.29 degrees, gamma =110.83 degrees, R1=6.94; 1 da, Py(Aib4)2.et ac, C41H65N9O12.1.5H2O.C4H8O2, sp. gr. P1, a=16.064(4) A, b=16.156 A, c=21.655(5) A, alpha =90.14(1)degrees, beta=101.38(2) degrees, gamma=97.07(1)degrees, Z=4, R1=9.03; 1db, Py(Aib4)2.amylac, C41H65N9O12.H2O.C7H14O2, P2(1)/c, a=16.890(1) A, b=17.523(1)A, c=20.411(1) A, beta=98.18 degrees, Z=4, R=11.1 (with disorder).

Acetates↗

Self-assembling bis-dendritic peptides: design, synthesis and characterization of oxalyl-linked bis-glutamyl peptides [Glu(n)(CO2Me)n + 1-CO-]2; n = 1,3,7.

Three generations of glutamic acid dendrons [Glu(n),(CO2Me)n + 1; n = 1, 3, 7] have been joined together head-to-head by an oxalyl unit to form highly sterically congested bis-Glu-dendritic peptides with gelling properties. The single crystal X-ray structure of the first generation bis-dendritic peptide showed an extended hydrogen-bonded chiral tape with modest nonlinear optical activity.

Crystallography, X-Ray↗

The circadian pattern of ischaemic heart disease events in Indian population.

A circadian variation of the onset of almost all ischaemic heart disease (IHD) manifestations with an increased incidence between 6:00 a.m. to 12:00 noon has been reported in several publications during the last decade. This study included 605 patients of various IHD subgroups, i.e., acute Q-wave myocardial infarction (n = 174), unstable angina (n = 266), non-Q myocardial infarction (n = 67), acute pulmonary oedema (n = 35) and sudden cardiac death (n = 63) proven to be due to IHD by electrocardiogram and/or autopsy. In overall, 33.55% (p < 0.0001) of patients had the IHD events with an increased frequency between 6:00 a.m. To 12:00 noon (2nd quarter of the day.) The distribution in the remaining, 1st 3rd and 4th quarters was 22.64%, 20.99% and 22.80%, respectively. Similar circadian rhythm (2nd quarter peak) was seen in males (n = 486), females (n = 119), patients ages < 60 years (n = 388), patients without past history of IHD (n = 434) and in those not on any medications (n = 359). However in patients with past history of IHD and diabetics, the circadian distribution did not differ from the random and the cases were distributed almost evenly in all the four quarters of the day. 39.08% of all the acute Q wave myocardial infarction (A-QMI), 33.45% of unstable angina and 36.5% of sudden cardiac deaths also occurred between 6:00 a.m. and 12:00 noon. However 51.42% cases of acute pulmonary oedema were encountered in the 4th quarter of the day and patients with non Q-myocardial infarction (non-QMI) did not show any particular pattern in relation to circadian rhythm. Thus it was inferred that in Indian population too the circadian pattern of IHD manifestations are similar to other population studies and morning appears to be the time, when the triggers (transient precipitating risk factors) that lead to these events are likely to be prominent. Study of these triggers and/or early morning pathophysiological changes may go a long way in understanding ischaemic heart disease and suggesting possible means of prevention.

Angina Pectoris↗

Core directed self-assemblies in the solid state of retro Aib bis-peptide dicarboxylic acids; a design strategy for control of molecular orientation in peptides.

Self-assembly patterns as a function of the central core insert in the retro bis-peptide dicarboxylic acids HO-Aib-X-Aib-OH, containing oxalyl (-CO-CO-; 1), fumaryl (-CO-CH = CH-CO-; 2), and adipoyl [-CO-(CH2)4-CO-; 3], have been characterized by single crystal x-ray diffraction analyses. Extensive hydrogen bonding occurs in each crystal but there are no OH ... O binds between acid groups. Only two types of hydrogen bonds occur in all the crystals: NH ... O (acid terminal), 2.84-2.98 A and OH (acid terminal) ... O (core carbonyl), 2.55-2.67 A (except for an additional intramolecular C5 type bond in the oxalyl moiety in 1). The self-assembly patterns are a beta-network in 1, separate layer assemblies (beta-networks) for two independent molecules in 2 that combine into a three-dimensional gamma network, and separate ribbon assembles (alpha networks) for two independent molecules in 3 that combine into an extended beta-network sheet with hydrophobic faces.

Amino Acid Sequence↗

The delineation of hydrogen-bonding patterns in supramolecular self-assembly of several core oxalo retro-peptides and crystal structure of MeO-Ser-Leu-COCO-Leu-Ser-OMe.

Pseudo-C5-type intramolecular hydrogen bonding, arising from the C2 disposition of the core NH-CO-CO-NH unit in oxalo retro-peptides, is formed in addition to extended hydrogen bonding with neighbors forming sheets in MeO-Aib-COCO-Aib-OMe (1), helices in MeO-Leu-COCO-Leu-OMe (2) and ribbons in MeO-Ser-Leu-COCO-Leu-Ser-OMe (3). In 3 the OH in the Ser side-chains form hydrogen bonds with the backbone carbonyl of Leu groups from neighboring molecules. Crystal parameters for 3 are: C22H38N4O10, monoclinic, space group P2(1), a = 7.374(1), b = 18.218(4), c = 10.661(3) A, beta = 95.72(2) degrees, R = 0.063 for 1738 observed reflections with [formula: see text].

Crystallography, X-Ray↗

Polymethylene spacer linked bis(Ala) peptides form modified beta-sheet structures. Crystal structure and self-assembly pattern of adipoyl and suberoyl analogues.

The adipoyl- and suberoyl-linked bis(Ala) peptides have an extended backbone between the two C alpha atoms in each molecule. They self-assemble, through intermolecular hydrogen bonds and stacking of parallel strands, into highly ordered modified beta-sheet-like structures. Crystals data for adipoyl bis(Ala)diester are as follows: C14H24N2O6, monoclinic space group P2(1), a = 4.900(1), b = 29.093(10), c = 6.021(2) A, beta = 104.20(2) degrees, R = 0.053 for 1100 data > 3 sigma (F); for suberoyl bis(Ala)diester: C16H28N2O6, monoclinic space group P2(1), a = 4.887(2), b = 32.650(9), c = 6.004(2) A, beta = 103.79(3), R = 0.070 for 1065 data > 3 sigma (F).

Adipates↗

Methanol-mediated, modular self-assembly of antiparallel beta-dimers. Crystal structure of C alpha backbone-modified tripeptide Bz-Aib-NHCOCO-Aib-OMe.

The backbone-modified tripeptide Bz-Aib-NHCOCO-Aib-OMe, in which the central C alpha has been replaced with CO, self-assembles in the solid state into highly ordered two-dimensional arrays through MeOH mediated intermolecular stacking of dimeric 'disk' modules formed by an antiparallel beta-sheet-type arrangement of tripeptide molecules. The C alpha(C'O)N(C'O)(C')NC alpha segment is nearly coplanar (average deviation from a mean least-square plane is +/- 0.037 A). The oxalyl moiety forms two pseudo-C5 intramolecular hydrogen bonds. Crystal parameters are as follows: C18H23N3)6.CH3OH, triclinic space group P1-, alpha = 9.796(4), b = 10.348(3), c = 11.836(4) A, alpha = 78.28(3), beta = 73.72(3), gamma = 69.45(3), R = 0.082 for 1747 reflections measured with [formula: see text].

Crystallography, X-Ray↗