Nonsilyl Bicyclic Secondary Amine Catalysts for the Asymmetric Transfer Hydrogenation of α,ß-Unsaturated Aldehydes.

The first chiral synthesis of nonsilyl bicyclic secondary amine organocatalysts and their application to the asymmetric transfer hydrogenation of α,ß-unsaturated aldehydes are disclosed. A lower catalytic loading (5 mol %) is demonstrated for the reduction of a wide range of α,ß-unsaturated aldehydes (up to 97% yield and up to 99% ee). The application of this scalable methodology is showcased for the asymmetric synthesis of bioactive molecules such as phenoxanol, citronellol, ramelteon, and terikalant.

Metal- and Solvent-Free Multicomponent Decarboxylative A3-Coupling for the Synthesis of Propargylamines: Experimental, Computational, and Biological Investigations.

Decarboxylative A3-coupling of ortho-hydroxybenzaldehydes, secondary amines, and alkynoic acids is performed under catalyst and solvent-free conditions. The developed methodology provided a waste-free method for the synthesis of hydroxylated propargylamines which are versatile precursors for various bioactive heterocyclic scaffolds. The experimental and density functional theory studies revealed that the in situ-formed ortho-quinonoid intermediate (formed from ortho-hydroxybenzaldehyde and amine) undergoes a concerted Eschweiler-Clarke type decarboxylation with alkynoic acids. The synthesized compounds were evaluated for MAO-A, MAO-B, and AChE inhibitory activities as potential drug candidates for the treatment of various neurological disorders. Compound 4f was found to be the most potent and selective MAO-B (high selectivity over MAO-A) and AChE inhibitor in the series with IC50 values of 4.27 ± 0.07 and 0.79 ± 0.03 µM, respectively.

Vitamin D: A Modulator of Allergic Rhinitis.

Allergic rhinitis is a topic of concern among clinicians. Despite of being treated in form of oral medicines, nasal drops and sprays several patients come back with complaint of no relief. This necessitates to review and focus on etiology and to find some other treatment regimen. Established relation of serum vitamin D level and various allergic conditions attracts us to use it as a therapeutic agent for allergic rhinitis. It is a case-control observational study recruited 80 subjects with 40 cases and 40 controls. There was drop out of two subjects among cases. Cases were supplement with oral vitamin D (cholecalciferol-1000 IU OD) and controls received no treatment. Serum vitamin D level, Total nasal symptom score (TNSS) and total eosinophilic count (TEC) were calculated at 0, 1 and 3 months and compared. Pre-treatment average serum vitamin D level of cases was 20.15 + 10.26 ng/ml and of control was 27.94 + 13.38 ng/ml. The TNSS score of cases was 7.43 + 1.87 and of controls was 5.00 + 1.52. TEC of cases was 546.15 + 113.39 and of controls was 313.33 + 125.08. Post-treatment serum vitamin D level of cases was 38.05 + 14.62 and of controls was 27.43 + 12.76. TNSS of cases was 3.53 + 0.68 and 4.43 + 1.17 in control group, TEC of cases was 68.13 + 38.95 and of controls was 197.03 + 123.36. This study concludes that vitamin D acts as disease modulator in allergic rhinitis In case of allergic rhinitis with vitamin D deficiency its supplementation gives symptomatic relief and also lowers down the values of TNSS and TEC.

Alkaloids from Toddalia aculeata.

Two alkaloids N-methyl-4-hydroxy-7-methoxy-3-(2,3-epoxy-3-methylbutyl)-1H-quinolin-2-one (1) and 3-(2,3-dihydroxy-3-methylbutyl)-4,7-dimethoxy-1-methyl-1H-quinolin-2-one (2a) have been isolated from CH(2)Cl(2):methanol (1:1) and methanol extracts of leaves and stems of Toddalia aculeata. Their structures along with that of 15 other compounds, of which three are isolated for the first time from genus Toddalia, were established by their detailed spectral studies including 2D NMR viz. (1)H-(1)H COSY, (1)H-(13)C COSY, and HMBC.

Design, synthesis and in vitro cytotoxic studies of novel bis-pyrrolo[2,1][1,4] benzodiazepine-pyrrole and imidazole polyamide conjugates.

The design, synthesis and biological evaluation of novel pyrrolo [2,1][1,4] benzodiazepine (PBD) dimers 38-43 linked with pyrrole and imidazole polyamides from either side by a flexible methylene chain of variable length are described, which involved mercuric chloride mediated cyclization of the corresponding amino diethyl thioacetals. The compounds were prepared with varying numbers of pyrrole and imidazole containing polyamides to determine the structural requirements for optimal in vitro antitumor activity. These compounds were tested against a panel of 60 human cancer cells by the National Cancer Institute, and demonstrated that, of the compounds bis-PBD-pyrrole polyamides (38-40) and bis-PBD-imidazole polyamides (41-43) certain of the bis-PBD-pyrrole and imidazole polyamide conjugates are active for individual cancer cell lines (Table 1). However, this study found that bis-PBD-pyrrole and imidazole polyamide conjugates 38-43 in general are potent against many human cancer cell lines.

Solution- and solid-phase synthesis of natural product-like tetrahydroquinoline-based polycyclics having a medium size ring.

A solid-phase synthesis of tetrahydroquinoline-derived polycyclic 4, having a medium size ring with an enamide functionality, was achieved from tetrahydroquinoline derivative 3 in five steps with overall 40-45% yield. An enantiopure, tetrahydroquinoline-derived beta-amino ester, 1, was converted into compound 2 that has a free phenolic hydroxyl group as an anchoring site for solid-phase synthesis. The solid-phase worked well for this sequence, in which the synthesis of the unsaturated eight-membered enamide lactam was obtained by a ring-closing metathesis approach. Compound 4 is a novel, natural product-like polycyclic derivative that could further be utilized in library generation for developing small molecule chemical probes.

Methionine sustituted polyamides are RNAse mimics that inhibit translation.

RNAse mimics are small molecules that can cleave RNA in a fashion similar to ribonucleases. These compounds would be very useful as gene specific reagents if their activities could be regulated and targeted. We demonstrate here that polyamides with methionine substituents show enhanced RNA cleavage activity relative to other polyamides. Conjugation of these compounds to aminoglycosides produced RNAse mimics that are capable of inhibiting eukaryotic protein synthesis. As a new class of compounds capable of interacting with nucleic acids, these novel aminoglycoside-polyamides constitute promising scaffolds for the construction of nuclease mimics with biological activity.

Synthesis and in vitro cytotoxicity studies of novel L-tryptophan-polyamide conjugates and L-tryptophan dimers linked with aliphatic chains and polyamides.

The synthesis and biological evaluation of novel L-tryptophan pyrrole, imidazole polyamide conjugates (16-21), L-tryptophan-glycosylated pyrrole polyamide conjugates (28-30), L-tryptophan dimers (37-42) with straight carbon links of varying length, and L-tryptophan dimers (68-73) linked with pyrrole and imidazole polyamide from both sides by a flexible methylene chain of variable length are described. The compounds were prepared with varying numbers of pyrrole- and/or imidazole-containing polyamides and glycosylated pyrrole polyamides to determine the structural requirements for optimal in vitro antitumor activity. The compounds listed in Table 1 have been evaluated in a three cell line, one dose primary anticancer assay. The compounds listed in Table 2 have been evaluated against nine panels of 60 human cancer cell lines including leukemia, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, and breast cancer. It is observed from the initial cytotoxic data (Table 1) that compounds 16-19, 28-30, 68-69, and 71-73 have varying cytotoxic potencies against the three cancer cell lines. It is also observed, from the biological data from Table 2 for compounds 20-21, 37-42, and 70 against the 60 different tumor cells, that the L-tryptophan dimers 37-42 linked by a different number of carbon chains are more active than the L-tryptophan dimers linked by pyrrole or imidazole polyamides. The cytotoxic potency in tryptophan dimers, linked by a different number of carbon atoms increased the number of carbons between the two L-tryptophan rings.

Design, synthesis and in vitro cytotoxicity studies of novel pyrrolo [2,1][1,4] benzodiazepine-glycosylated pyrrole and imidazole polyamide conjugates.

The design, synthesis and biological evaluation of novel pyrrolo [2,1][1,4] benzodiazepine-water insoluble 31-38 and water soluble 39-46 glycosylated pyrrole and imidazole polyamide conjugates are described that involved mercuric chloride mediated cyclization of the corresponding amino diethyl thioacetals. The compounds were prepared with varying numbers of pyrrole and imidazole containing polyamides and incorporating glucose moieties in order to improve the water solubility of PBD-polyamide conjugates and probe the structural requirements for optimal in vitro antitumor activity. These compounds were tested against a panel of 60 human cancer cells by the National Cancer Institute, and demonstrated that the water soluble PBD-polyamide compounds exhibited a higher level of cytotoxic activity than the existing natural and synthetic pyrrolo [2,1-c][1,4] benzodiazepines. The cytotoxic activities of these compounds dramatically increase after hydrolysis of their acetylated counterparts. The activity data summarized in Table 1 and Table 2 show that the solubility of the PBD-polyamides and also the type of heterocycle play important roles influencing the cytotoxic activity of the PBD-polyamide conjugates. The PBD-glycosylated polyamide (water soluble) conjugates 39-46 are highly cytotoxic against many human cancer cell lines in comparison with the PBD-polyamide (water insoluble version) conjugates.

Synthesis and cytotoxicity evaluation of novel C7-c7, C7-N3 and N3-N3 dimers of 1-chloromethyl-5-hydroxy-1,2-dihydro-3H-benzo[e]indole (seco-CBI) with pyrrole and imidazole polyamide conjugates.

The C7-C7, C7-N3 and N3-N3 dimers of 1-chloromethyl-5-hydroxy-1,2-dihydro-3H-benzo[e]indole (seco-CBI) with pyrrole and imidazole polyamides were synthesized and preliminary anti-cancer evaluation carried out by NCI against three types of cancer cells.

Recent developments in novel pyrrolo[2,1-c][1,4]benzodiazepine conjugates: synthesis and biological evaluation.

The biological activity of many low molecular weight antitumor compounds appear to be related to their mode and specificity of interaction with particular DNA sequences. Such small molecules are of considerable interest in chemistry, biology and medicine. Most of the anticancer drugs employed clinically exert their antitumor effect by inhibiting nucleic acid (DNA or RNA) or protein synthesis. Inhibition can occur for example through cross-linking of bases in DNA or binding to and inactivation of enzymes necessary for the synthetic processes. It is evident that DNA is an important cellular target for many anticancer agents. Much information has been obtained from molecular genetics, i.e. replication of DNA and its transcription to RNA, which provides the template for protein synthesis. DNA is a well-characterized intracellular target but its large size and sequential nature makes it an elusive target for selective drug action. Binding of low molecular weight ligands to DNA causes a wide variety of potential biological responses. In this context PBDs (pyrrolo[2,1-c][1,4]benzodiazepines), a group of potent naturally occurring antitumor antibiotics produced by various Streptomyces species, are one of the most promising types of lead compounds. They differ in the number, type and position of substituent in both their aromatic A-ring and Py C-rings, and in the degree of saturation of the C-rings which can be either fully saturated or unsaturated at either C2-C3 (endocyclic) or C2 (exocyclic). There is either an imine or carbinolamine methyl ether at the N10-C11 position. This latter is an electrophilic center responsible for alkylating DNA. In the search for compounds with better antitumor selectivity and DNA sequence specificity many PBD analogues have been synthesized in an attempt to increase their potency against tumor cells. We review here recent progress on pyrrolo[2,1-c][1,4]benzodiazepine (PBDs) analogues and their conjugates, also the progress and developments of PBD conjugates with polyamides (information reading molecules in the minor groove of DNA). For example, the cross-linking efficiency of PBD dimers is much greater than that of other cross linkers including cisplatin and melphalan. A large number of PBD dimers and polyamide conjugates with varying linker lengths and bearing different heterocycles at different positions in the PBD ring synthesized in our group and their pharmacological properties have been reviewed.

Synthesis and antitumor cytotoxicity evaluation of novel pyrrolo[2,1-c][1,4]benzodiazepine imidazole containing polyamide conjugates.

The design, synthesis, and biological evaluation of novel C-8 linked pyrrolo[2,1-c][1,4]benzodiazepine (PBD)-imidazole polyamide conjugates (1-5) are described that involve mercuric chloride-mediated cyclization of the corresponding amino diethyl thioacetals. The compounds were prepared with varying numbers of imidazole- and pyrrole-containing polyamides in order to probe the structural requirements for optimal in vitro antitumor activity. These compounds were tested against a panel of human cancer cells by the National Cancer Institute, demonstrating that the compounds exhibited a higher level of cytotoxic activity than the existing natural and synthetic pyrrolo[2,1-c][1,4]benzodiazepines. The data presented show that the length of the polyamides and also the type of heterocycle play important roles in this series of compounds for anticancer activity. Compounds 1, 2, 3, and 5 have significant cytotoxic activity against the various types of cancer cell lines. It appears that cytotoxic activity is related to both the length and the heterocycles of the polyamides. Compound 1 exhibited a wide spectrum of anticancer activities against all cell lines in nine cancer panels and was especially effective against colon cancer, melanoma, and renal cancer and breast cancer, however, compound 4 did not exhibit any significant anticancer activity. This study found that PBD-imidazole polyamide conjugates are highly cytotoxic against many human cancer cell lines in comparison with the PBD-pyrrole polyamide conjugates.

Design and synthesis of bis 1-chloromethyl-5-hydroxy-1,2- dihydro-3H-benz[e]indole (seco-CBI)-pyrrole polyamide conjugates.

[carbohydrate structure: see text] The design and synthesis of bis 1-chloromethyl-5-hydroxy-1,2-dihydro-3H-benz[e]indole (seco-CBI)-pyrrole polyamide conjugates (13, 17) as DNA minor groove binding agents are described.