Synthesis of Novel Cyclized C3-Azoles of Galeterone for Prostate Cancer Therapy

In the steroidogenesis pathway, cholesterol undergoes two major modifications at the C17 and C3 positions for the biosynthesis of adrenal (male sex hormones) and gonadal (mineralocorticoids) hormones. The C17–hydroxylation /17,20-lyastion and C3-hydroxy oxidation are catalyzed by CYP17A1 and 3β−HSD enzymes respectively. The formation of C3-oxo metabolite by 3β−HSD is essential for the further metabolism at C5 double bond by 5α-SRD enzyme to produce dihydrotestosterone (DHT), a most potent androgen. These androgenic metabolites are important for the development and maintenance of male sex characters. The abnormal production of androgens and their aberrant interaction with androgen receptor is known for the development and progression of prostate cancer disease. Clinical anti-PC agents abiraterone and galaterone are 3-OH-Δ5-C17-heterocycles substituted steroids. Both agents exert their potent anti-PC activity by reducing androgen biosynthesis through CYP17A1 enzyme inhibition. Due to their structural similarities to endogenous steroids they also undergo metabolism at C3 position by 3β−HSD. Consequently, these two agents have short half-life on oral administration (t1/2~1h). Moreover, both agents suffer from low oral bioavailability (abi-37% and gal-19%), and thus require very high dose to show clinical efficacy. To prevent metabolism by 3- HSD and further by 5-SRD enzymes, the metabolic soft-spot (C3–OH) was appended with imidazole ring to obtain metabolically stable agents with no compromise in anti-prostate cancer properties. This modification (VNPP433-3β) has significantly improved half-life (31 h) which is 24.75-fold superior to Gal’s half-life. Additionally, VNPP433-3β has improved oral absorption of 49.6% bioavailability which is 2.96 superior to Gal’s oral absorption. In the current research we have synthesized various C3-azole compounds such as tetrazoles, triazoles, and diazole using cyclization method on stereospecific azide and amine intermediates. These newly synthesized compounds are under biological activity evaluation. We will be presenting rational behind the design novel C3 azoles, their synthetic detail, and pharmacokinetic data of our lead compound and possibly anti-cancer properties of compounds under study

ANALYSIS AND STRUCTURAL OPTIMIZATION OF 5 TON H-FRAME HYDRAULIC PRESS

Abstract Using the optimum resources possible in designing the hydraulic presses frame can effect reduction in the cost of the hydraulic presses. By optimizing the weight of material utilized for building the structure. An attempt has been made in this direction to reduce the volume of material. So here we consider an industrial application project consisting of mass minimization of H-frame type hydraulic press. This press has to compensate the forces acting on the working plates and has to fulfill certain critical constraints. ANSYS has been used for this analysis the main aim is to reduce the cost of the Hydraulic presses without compromising on the quality of the output. With regarding to design specification, stress distribution, deflection, and cost, are focused on optimized design. The methodology followed in this work is comparison of stresses induced in machine for different thickness used for construction of frame and column of the Hframe type hydraulic press.

Stability of Assemblies

High level assembly plans prescribe the sequence in which parts come together along with their motions. At each stage of assembly the stability of subassemblies is an important concern. In this paper we address the problem of gravitational stability of assemblies of frictionless rigid bodies. Solution methods to the problems of determining if an assembly is stable, and finding a stable orientation for a given assembly are proposed. The solution methods for the two problems compute constrained motions of individual parts that decrease gravitational potential energy, in order to determine stability and search for stable orientations. Linear programming is used to obtain numerical solutions. The problem of finding a stable orientation is formulated as a maximin problem. The solution to this problem is the first general method for automatically determining stable orientations. The program to solve the two problems takes as input a geometric model of the assembly and information related to ..

Analysis of Restraints to Translational and Rotational Motion from the Geometry of Contact

The automatic generation of high-level assembly plans from geometric models makes extensive use of restraints imposed by components on one another. The geometry of contact can be used to find the nature of these restraints. In this paper, we present a method to determine restraints to translational and rotational motion of planar as well as 3-D objects. A set of parameters that represent any possible translational/rotational motion is identified. A geometric representation of the space of motion parameters (M a) is created. Restraints due to individual mating surface elements are computed by identifying subspaces in M a which represent motion parameters that are ‘disallowed’ due to the contact. These are then superposed to generate the required solution. Restraints that are redundant are easily identified and are not computed. Information about restraints is used extensively in assembly planning - to determine degrees-of-freedom of components and subassemblies, to analyze the stability of subassemblies, to plan proper grasps, etc. We believe that the proposed representation can be used effectively in making these evaluations, taking us closer to generating correct assembly plans.</p

Impending Motion Direction of Contacting Rigid Bodies

Three different formulations are presented for expressing the initial motion direction of a system of contacting frictionless rigid bodies under gravity. The bodies are assumed to have no initial velocity. The first formulation expresses the accelerations of the bodies in terms of the contact forces between the bodies. The contact forces are themselves expressed as the solution to a quadratic programming problem. The second formulation expresses the accelerations of the bodies according to Gauss&apos; &quot;principle of least constraint.&quot; This principle is well-known to apply to systems with holonomic motion constraints (such as joints or hinges); in this paper, we show that the principle extends to the nonholonomic constraints that arise due to contact between bodies. The third formulation is conceptually the simplest; it says simply that the initial acceleration of the system is in the direction that most quickly decreases the gravitational potential energy of the system without violating the ..