Steven B. Larson

Bio: Steven B. Larson is an academic researcher from Brigham Young University. The author has contributed to research in topics: Inosine & Pyridine. The author has an hindex of 16, co-authored 59 publications receiving 829 citations.

Thiazolo[4,5-d]pyrimidine nucleosides. The synthesis of certain 3-beta-D-ribofuranosylthiazolo[4,5-d]pyrimidines as potential immunotherapeutic agents.

Abstract: Novel analogues of the naturally occurring purine nucleosides were synthesized in the thiazolo[4,5-d]pyrimidine ring system to determine the immunomodulatory effects of insertion of a sulfur atom in place of nitrogen at position 7 of the purine ring. In particular, 5-amino-3-beta-D-ribofuranosylthiazolo[4,5-d]pyrimidine-2,7(3H,6H) -dione (7, guanosine analogue), 3-beta-D-ribofuranosylthiazolo[4,5-d]pyrimidine-2,5,7(3H,4H,6H) trione (8, xanthosine analogue), 3-beta-D-ribofuranosylthiazolo[4,5-d]pyrimidine-2,7(3H,6H)-dione (10, inosine analogue), and 7-amino-3-beta-D-ribofuranosylthiazolo[4,5-d]pyrimidin-2(3H)-one (32, adenosine analogue) were prepared, as well as the 8-mercaptoguanosine (14) and 6-mercaptoguanosine (17) analogues. Single-crystal X-ray studies confirmed the structural assignment of 17 and 32 as having the beta-configuration with the site of glycosylation at N3. The nucleosides were evaluated for their ability to potentiate various murine immune functions in direct comparison to the known active agents 8-bromoguanosine (1), 8-mercaptoguanosine (2), and 7-methyl-8-oxoguanosine (3). Two of the guanosine analogues, 7 and 14, were found to exhibit significant immunoactivity relative to the positive control compounds (1-3), while the adenosine, inosine, xanthosine, and 6-mercaptoguanosine analogues were devoid of activity. Compound 7 exhibited greater immunoactivity than any of the other guanosine analogues and derivatives in all test systems. Specifically, 7 was shown to be about twice as potent as 3 in the murine spleen cell mitogenicity assay. In addition, treatment with 7 produced about a 4-fold increase in natural killer cell cytotoxicity, while treatment with 3 afforded a 3-fold increase over controls. Finally, 7 provided excellent protection (92% survivors compared to 0% for placebo controls) against Semliki Forest virus in mice. Induction of interferon may account for the major mode of action of these guanosine analogues.

Growth inhibition and induction of cellular differentiation of human myeloid leukemia cells in culture by carbamoyl congeners of ribavirin.

Abstract: A series of 1,2,3-triazole (2), pyrazole (3 and 5), and pyrrole (4) ribonucleosides with two adjacent carbamoyl groups have been synthesized and evaluated for cell growth inhibition and induction of cellular differentiation of HL-60 cells in culture. Glycosylation of the TMS derivatives of dimethyl 1,2,3-triazole-4,5-dicarboxylate (6) and diethyl pyrazole-3,4-dicarboxylate (7) with 1-O-acetyl-2,3,5-tri-O-benzoyl-D- ribofuranose (8) in the presence of TMS triflate gave predominantly the beta-nucleosides 9 and 14, respectively. Ammonolysis of 9 and 14 furnished 2-beta-D-ribofuranosyl-1,2,3-triazole-4,5-dicarboxamide (2) and 1-beta-D-ribofuranosylpyrazole-3,4-dicarboxamide (3), respectively. Stereoselective ring annulation of 1-deoxy-1-hydrazinyl-2,3-O-isopropylidene-D- ribose (16) with tetracyanoethylene (15) gave 5-amino-1-(2,3-O-isopropylidene-beta-D-ribofuranosyl)pyrazole-3,4- dicarbonitrile (17). Deisopropylidenation of 17, followed by oxidative hydrolysis of the reaction product (18), gave the 5-amino derivative of 3 (5). Stereospecific glycosylation of the sodium salt of preformed diethyl pyrrole-3,4-dicarboxylate (22) with 1-chloro-2,3-O-isopropylidene-5-O-(tert-butyldimethylsilyl)-alpha-D- ribofuranose (23) was accomplished to furnish blocked nucleoside 24, which on ammonolysis and deisopropylidenation gave 1-beta-D-ribofuranosylpyrrole-3,4-dicarboxamide (4). The structures of 2 and 3 were assigned by single-crystal X-ray diffraction studies, which showed extensive inter- and intramolecular hydrogen bonding. Nucleosides 2-5 are devoid of significant cytotoxic properties against L1210 and WI-L2 leukemia cells in culture. However, these compounds were found to be inducers of cellular differentiation of HL-60 cells in the range of 30-60 microM and were comparable to ribavirin in this regard.

Antitumor and antiviral activity of synthetic alpha- and beta-ribonucleosides of certain substituted pyrimido[5,4-d]pyrimidines: a new synthetic strategy for exocyclic aminonucleosides.

Abstract: A novel and direct synthesis of the antiviral and antitumor agent 4-amino-8-(beta-D-ribofuranosylamino)pyrimido[5,4-d]pyrimidine (ARPP, 8) and its alpha-anomer (11) has been developed. Treatment of 2,4,6,8-tetrachloropyrimido[5,4-d]pyrimidine (1) with 2,3-O-isopropylidene-D-ribofuranosylamine gave an anomeric mixture of 2,4,6-trichloro-8-(2,3-O-isopropylidene-beta- and -alpha-D-ribofuranosylamino)pyrimido[5,4-d]pyrimidines (3 and 4) in a ratio of 1.0:0.7. A nucleophilic displacement of the 4-chloro group of 3 and 4 with NH3 furnished 4-amino-2,6-dichloro-8-[(2,3-O-isopropylidene-beta-D-ribofuranosyl)amino ] pyrimido[5,4-d]pyrimidine (6) and its alpha-anomer (9), respectively. Catalytic hydrogenation of 6 and 9, followed by deisopropylidenation gave ARPP (8) and the alpha-anomer 11, respectively. Similarly, 3 and 4 have been transformed to 4-methoxy-8-(beta-D-ribofuranosylamino)pyrimido-[5,4-d]pyrimidine (MRPP, 14) and its alpha-anomer (17). Application of this procedure to 3 with NH2Me or NHMe2 resulted in the synthesis of 4-(methylamino)- and 4-(dimethylamino)-8-(beta-D-ribofuranosylamino)pyrimido [5,4-d]pyrimidine (24 and 27, respectively). A synthesis of 8-(beta-D-ribofuranosylamino)pyrimido[5,4-d]pyrimidin-4(3H)-one (21) has also been accomplished from 3 in three steps. Selective hydrogenation of 6 furnished 4-amino-6-chloro-8-[(2,3-O-isopropylidene-beta-D-ribofuranosyl)amino] pyrimido[5,4-d]pyrimidine (36), the structure of which was established by single-crystal X-ray diffraction analysis. Deisopropylidenation of 36 gave 6-chloro-ARPP (37). Extended treatment of 36 with NH3 furnished 4,6-diamino-8-[(2,3-O-isopropylidene-beta-D-ribofuranosyl)amino]pyrimido [5,4-d]pyrimidine (34), which on deisopropylidenation gave 6-amino-ARPP (35). An unambiguous synthesis of 34 and 36 has also been accomplished by the reaction of 4,6,8-trichloropyrimido[5,4-d]pyrimidine (28) with 2, followed by the treatment with NH3. Nucleophilic displacement studies with 1, 6, and 28 indicated the reactivity of the halogens in these compounds is in the order of 8 greater than 4 greater than 6 greater than 2. The structures of 3 and 9 have been assigned on the basis of 1H NMR data and further confirmed by single-crystal X-ray diffraction analysis. The exocyclic aminonucleosides synthesized during this study were tested for their activity against several RNA and DNA viruses in vitro and against L1210, WI-L2, and LoVo/L in cell culture. The effect of these compounds on the de novo nucleic acid biosynthesis has been studied. Compound 14 (MRPP) exhibited enhanced activity against L1210 in vivo, when compared to ARPP (8).

Synthesis and biological evaluation of certain C-4 substituted pyrazolo[3,4-b]pyridine nucleosides.

Abstract: A series of C-4 substituted pyrazolo[3,4-b]pyridine nucleosides have been synthesized and evaluated for their biological activity. Successful synthesis of various C-4 substituted pyrazolo[3,4-b]pyridine nucleosides involves nucleophilic displacement by a suitable nucleophile at the C-4 position of 4-chloro-1H-pyrazolo[3,4-b]pyridine (5), followed by glycosylation of the sodium salt of the C-4 substituted pyrazolo[3,4-b]pyridines with a protected alpha-halopentofuranose. Use of this methodology furnished a simple and direct route to the beta-D-ribofuranosyl, beta-D-arabinofuranosyl, and 2-deoxy-beta-D-erythro-pentofuranosyl nucleosides of C-4 substituted pyrazolo[3,4-b]pyridines, wherein the C-4 substituent was azido, amino, methoxy, chloro, or oxo. The regiospecificity of these glycosylations was determined on the basis of UV data and the anomeric configuration was established by 1H NMR analysis. Conclusive structural assignment was made by a single-crystal X-ray diffraction study of three compounds, 15, 31, and 42, as representatives of ribo-2'-deoxy-, and aranucleosides, respectively. The stereospecific attachment of all three alpha-halogenoses appears to occur by a Walden inversion (SN2 mechanism) at the C-1 carbon of the halogenose by the anionic N-1 of pyrazolo[3,4-b]pyridine. All deprotected nucleosides were tested against various viruses and tumor cells in culture. The effects of these compounds on de novo purine and pyrimidine nucleotide biosynthesis was also evaluated. Among the compounds tested, 4-chloro-1-beta-D-ribofuranosylpyrazolo[3,4-b]pyridine (16) and 1-beta-D-ribofuranosyl-4,7-dihydro-4-oxopyrazolo[3,4-b]pyridine (19) were found to be moderately cytotoxic to L1210 and WI-L2 in culture.

Prediction of Hydrophobic (Lipophilic) Properties of Small Organic Molecules Using Fragmental Methods: An Analysis of ALOGP and CLOGP Methods

Abstract: Molecular hydrophobicity (lipophilicity), usually quantified as log P (the logarithm of 1-octanol/water partition coefficient), is an important molecular characteristic in drug discovery. ALOGP and CLOGP are two of the most widely used methods for the estimation of log P. This work describes an extensive reparametrization of the atomic log P values and a detailed comparison of the performance of ALOGP and CLOGP methods on the Pomona Medchem database. Only the “star list” compounds having precisely measured log P values were used in this analysis. While the overall results with both methods are similar, analysis shows that the CLOGP method is better for very small molecules in the range of 1−20 atoms. The two methods are almost comparable in the range of 21−45 atoms, while the ALOGP method has better accuracy for molecules with more than 45 atoms. Although the rms deviation and the correlation coefficient for CLOGP predictions were marginally better than those for corresponding ALOGP predictions, the latte...

Molecular basis for the immunostimulatory activity of guanine nucleoside analogs: activation of Toll-like receptor 7

Abstract: Certain C8-substituted and N7, C8-disubstituted guanine ribonucleosides comprise a class of small molecules with immunostimulatory activity. In a variety of animal models, these agents stimulate both humoral and cellular immune responses. The antiviral actions of these guanosine analogs have been attributed to their ability to induce type I IFNs. However, the molecular mechanisms by which the guanosine analogs potentiate immune responses are not known. Here, we report that several guanosine analogs activate Toll-like receptor 7 (TLR7). 7-Thia-8-oxoguanosine, 7-deazaguanosine, and related guanosine analogs activated mouse immune cells in a manner analogous to known TLR ligands, inducing cytokine production in mouse splenocytes (IL-6 and IL-12, type I and II IFNs), bone marrow-derived macrophages (IL-6 and IL-12), and in human peripheral blood leukocytes (type I IFNs, tumor necrosis factor alpha and IL-12). The guanosine congeners also up-regulated costimulatory molecules and MHC I/II in dendritic cells. Genetic complementation studies in human embryonic kidney 293 cells confirmed that the guanosine analogs activate cells exclusively via TLR7. The stimulation of TLR7 by the guanosine analogs in human cells appears to require endosomal maturation because inhibition of this process with chloroquine significantly reduced the downstream activation of NF-kappaB. However, TLR8 activation by R-848 and TLR2 activation by [S-[2,3-bis(palmitoyloxy)-(2-RS)-propyl]-N-palmitoyl-R-Cys-S-Ser-Lys4-OH, trihydrochloride)] were not inhibited by chloroquine, whereas TLR9 activation by CpG oligodeoxynucleotides was abolished. In summary, we present evidence that guanosine analogs activate immune cells via TLR7 by a pathway that requires endosomal maturation. Thus, the B cell-stimulating and antiviral activities of the guanosine analogs may be explained by their TLR7-activating capacity.

Pharmacological significance of triazole scaffold.

Abstract: The triazole nucleus is one of the most important and well known heterocycles which is a common and integral feature of a variety of natural products and medicinal agents. Triazole nucleus is present as a core structural component in an array of drug categories such as antimicrobial, anti-inflammatory, analgesic, antiepileptic, antiviral, antineoplastic, antihypertensive, antimalarial, local anaesthetic, antianxiety, antidepressant, antihistaminic, antioxidant, antitubercular, anti-Parkinson's, antidiabetic, antiobesity and immunomodulatory agents, etc. The broad and potent activity of triazole and their derivatives has established them as pharmacologically significant scaffolds. The basic heterocyclic rings present in the various medicinal agents are 1,2,3-triazole and 1,2,4-triazole. A large volume of research has been carried out on triazole and their derivatives, which has proved the pharmacological importance of this heterocyclic nucleus. The present paper is an attempt to review the pharmacological activities reported for triazole derivatives in the current literature with an update of recent research findings on this nuclei.

Electrochemical oxidation and structural changes of 5,6-dihydrobenzo[c]cinnolines

Abstract: The location of energy minima on the conformational energy surface of molecules by computational methods (conformational searching) continues to play a key role in computer-assisted molecular modeling. Although a number of conformational search procedures have been devised over the past several years, new more efficient methods are urgently needed if molecules with increased complexity are to be treated in a quantitative manner. In this paper we describe a method, termed low-mode search (LMOD), which is based on eigenvector following (or mode following), for the exhaustive exploration of the potential energy hypersurface of molecules. It is particularly efficient at searching the conformational space of both cyclic and acyclic molecules, and we describe its effectiveness for a number of conformational search problems including acyclic, monocyclic, and bicyclic hydrocarbons and cyclic pentapeptides. No special treatment of rings in cyclic molecules is necessary, nor is it necessary to define rotatable bond...