A planning strategy for diversity-oriented synthesis

In contrast to target-oriented synthesis (TOS) and medicinal or combinatorial chemistry, which aim to access precise or dense regions of chemistry space, diversity-oriented synthesis (DOS) populates chemical space broadly with small-molecules having diverse structures. The goals of DOS include the development of pathways leading to the efficient (three- to five-step) synthesis of collections of small molecules having skeletal and stereochemical diversity with defined coordinates in chemical space. Ideally, these pathways also yield compounds having the potential to attach appendages site- and stereoselectively to a variety of attachment sites during a post-screening, maturation stage. The diverse skeletons and stereochemistries ensure that the appendages can be positioned in multiple orientations about the surface of the molecules. TOS as well as medicinal and combinatorial chemistries have been advanced by the development of retrosynthetic analysis. Although the distinct goals of DOS do not permit the application of retrosynthetic concepts and thinking, these foundations are being built on, by using parallel logic, to develop a complementary procedure known as forward-synthetic analysis. This analysis facilitates synthetic planning, communication, and teaching in this evolving discipline.     

A highly efficient synthesis of antiobestic ligand GW501516 for the peroxisome proliferator-activated receptor δ through in situ protection of the phenol group by reaction with a Grignard reagent

A new synthesis of an agonist for the peroxisome proliferator-activated receptor δ (PPARδ) GW501516 as a potential antiobesity drug is described. The synthetic route involves the in situ protection of the phenol group with a Grignard reagent and a regio-controlled one-pot reaction for the formation of a sulfide bond as the key step. Starting from commercially available 4-iodo-2-methylphenol, this approach affords GW501516 with an overall yield of 87%.     

Molecular modeling of cytochrome P450 3A4

The three-dimensional structure of human cytochrome P450 3A4 was modeled based on crystallographic coordinates of four bacterial P450s: P450 BM-3, P450cam, P450terp, and P450eryF. The P450 3A4 sequence was aligned to those of the known proteins using a structure-based alignment of P450 BM-3, P450cam, P450terp, and P450eryF. The coordinates of the model were then calculated using a consensus strategy, and the final structure was optimized in the presence of water. The P450 3A4 model resembles P450 BM-3 the most, but the B helix is similar to that of P450eryF, which leads to an enlarged active site when compared with P450 BM-3, P450cam, and P450terp. The 3A4 residues equivalent to known substrate contact residues of the bacterial proteins and key residues of rat P450 2B1 are located in the active site or the substrate access channel. Docking of progesterone into the P450 3A4 model demonstrated that the substrate bound in a 6-orientation can interact with a number of active site residues, such as 114, 119, 301, 304, 305, 309, 370, 373, and 479, through hydrophobic interactions. The active site of the enzyme can also accommodate erythromycin, which, in addition to the residues listed for progesterone, also contacts residues 101, 104, 105, 214, 215, 217, 218, 374, and 478. The majority of 3A4 residues which interact with progesterone and/or erythromycin possess their equivalents in key residues of P450 2B enzymes, except for residues 297, 480 and 482, which do not contact either substrate in P450 3A4. The results from docking of progesterone and erythromycin into the enzyme model make it possible to pinpoint residues which may be important for 3A4 function and to target them for site-directed mutagenesis.     

Hydrolysis of new phthalimide-derived esters catalyzed by immobilized lipase

The last step of the production of four phthalimide-derived acids, designed to act as antiasthma drugs, was performed by enzymatic hydrolysis of the respective methyl or ethyl esters. The esters 4-ethyl-[2-(1,3-dioxo-1,3-dihydro-2-isoindoylyl)]-phenoxyacetic methyl ester (PHT-MET), 4-ethyl-[2-(1,3-dioxo-1,3-dihydro-2-isoindoylyl)]-phenoxyacetic ethyl ester, 4-(1,3-dioxo-1,3-dihydro-2-isoindoylyl)-phenoxyacetic ethyl ester, and 2-(1,3-dioxo-1, 3-dihydro-2-isoindoylyl)-phenoxyacetic ethyl ester were hydrolyzed by immobilized lipase. The enzymatic reaction could be used only to produce the desired 4-substituted compounds. The best result that was found to hydrolysis of PHT-MET, and, therefore, that ester was selected for optimization experiments in a three-phase system. Reactions were performed with solid biocatalyst (Lipozyme® RM IM), organic solvent phase (ethyl acetate), and aqueous phase (saturated Na₂CO₃ solution). To optimize the reaction conditions, an experimental design optimization procedure was used. The variables studied were the amount of enzyme, the temperature, and the volume of the aqueous solution. Time course experiments were then performed for different initial enzyme concentrations (0.5, 0.9, and 1.4 U_H/mL of solvent). The optimized reaction conditions found were 20 mg of Lipozyme (0.9 U_H/mL_solvent) and 5.0 mL of Na₂CO_3(sat) at 40°C for 6 h.     

A very large diversity space of synthetically accessible compounds for use with drug design programs

We have constructed a very large virtual diversity space containing more than 10¹³ chemical compounds. The diversity space is built from about 400 combinatorial libraries, which have been expanded by choosing sizeable collections of suitable R-groups that can be attached to each link point of their scaffolds. These R-group collections have been created by selecting reagents that have drug-like properties from catalogs of available chemicals. As members of known combinatorial libraries, the compounds in the diversity space are in general synthetically accessible and useful as potential drug leads. Hence, the diversity space can be used as a vast source of compounds by a de novo drug design program. For example, we have used such a program to generate inhibitors of HIV integrase enzyme that exhibited activity in the micromolar range.     

A genetic algorithm for the automated generation of small organic molecules: Drug design using an evolutionary algorithm

Rational drug design involves finding solutions to large combinatorial problems for which an exhaustive search is impractical. Genetic algorithms provide a novel tool for the investigation of such problems. These are a class of algorithms that mimic some of the major characteristics of Darwinian evolution. LEA has been designed in order to conceive novel small organic molecules which satisfy quantitative structure-activity relationship based rules (fitness). The fitness consists of a sum of constraints that are range properties. The algorithm takes an initial set of fragments and iteratively improves them by means of crossover and mutation operators that are related to those involved in Darwinian evolution. The basis of the algorithm, its implementation and parameterization, are described together with an application in de novo molecular design of new retinoids. The results may be promising for chemical synthesis and show that this tool may find extensive applications in de novo drug design projects.     

药物不良反应的特点与预防

药物不良反应已成为全社会关注的热点，及时了解有关不良反应的情况并采取必要的预防措施，以保证患者用药安全，维护患者身体健康是医务工作者刻不容缓的任务。     

Spherical molecularly imprinted polymers (SMIPs) via a novel precipitation polymerization in the controlled delivery of sulfasalazine

Spherical molecularly imprinted polymers (SMIPs) have been prepared via a novel precipitation polymerization using sulfasalazine (prodrug used in the diseases of the colon) as template. The sulfasalazine was incorporated into SMIPs and into a spherical non-imprinted polymer (control), and then the release rate of the bioactive agent at different pH values was evaluated. Considerable differences in the release characteristics between imprinted and non-imprinted polymers have been observed. This opens the possibility of the development of drug release systems capable of modulating the release of a specific molecule. Photomicrography of spherical molecularly imprinted polymers (SMIPs).     

G-G base-pairing in nucleobase adducts of the anticancer drug cis-[PtCl2(NH3)(2-picoline)] and its trans isomer

cis-[PtCl2(NH3)(2-picoline)] (AMD473) is a sterically-hindered anticancer complex with a profile of chemical and biological activity that differs significantly from that of cisplatin. Adducts of AMD473 with neutral 9-ethylguanine (9-EtGH) and anionic (N1-deprotonated) 9-ethylguanine (9-EtG) as perchlorate and nitrate salts, and also a nitrate salt of the trans isomer (AMD443), were prepared and their structures determined by X-ray crystallography: cis-[Pt(NH3)(2-pic)(9-EtGH)2](ClO4)2 (1).2H(2)OMe(2)CO, cis-[Pt(NH3)(2-pic)(9-EtGH)2](NO3)2 (2).2H2O, cis-[Pt(NH3)(2-pic)(9-EtGH)(9-EtG)]NO3 (3),3.5 H2O, trans-[Pt(NH3)(2-pic)(9-EtGH)(9-EtG)]NO3 (4).8H2O. In all cases, platinum coordination is through N7 of neutral (1, 2) and anionic (3, 4) guanine. In each complex, the guanine bases are arranged in the head-to-tail conformation. In complex 1, there is an infinite array of six-molecule cycles, based on both hydrogen bonding and pi-pi stacking of the 2-picoline and guanine rings. Platinum(II) coordinated at N7 acidifies the N1 proton of neutral 9-ethylguanine (pKa = 9.57) to give pKa1 = 8.40 and pKa2 = 8.75 for complex 2, and pKa1 = 7.77 and pKa2 = 9.00 for complex 4. In complexes 3 and 4, three intermolecular hydrogen bonds are formed between neutral and deprotonated guanine ligands involving O6, N1 and N2 sites. Unusually, both of the platinated guanine bases of complexes 3 and 4 participate in this triple G triple bond G hydrogen bonding. This is the first report of X-ray crystal structures of nucleobase adducts of the promising anticancer drug AMD473.