Raouf A. Hussain

Discovery of 2-Chloro-N-(4-methoxyphenyl)-N-methylquinazolin-4-amine (EP128265, MPI-0441138) as a Potent Inducer of Apoptosis with High In Vivo Activity

Using a live cell, high-throughput caspase-3 activator assay, we have identified a novel series of 4-anilinoquinazolines as inducers of apoptosis. In this report, we discuss the discovery of 2-chloro-N-(4-methoxyphenyl)-N-methylquinazolin-4-amine, compound 2b (EP128265, MPI-0441138) as a highly active inducer of apoptosis (EC50 for caspase activation of 2 nM) and as a potent inhibitor of cell proliferation (GI50 of 2 nM) in T47D cells. Compound 2b inhibited tubulin polymerization, was effective in cells overexpressing ABC transporter Pgp-1, and was efficacious in the MX-1 human breast and PC-3 prostate cancer mouse models. In contrast to the SAR of 4-anilinoquinazolines as EGFR kinase inhibitors, the methyl group on the nitrogen linker was essential for the apoptosis-inducing activity of 4-anilinoquinazolines and substitution in the 6- and 7-positions of the quinazoline core structure decreased potency.

Sweetening agents of plant origin: phenylpropanoid constituents of seven sweet-tasting plants

Field inquiries and organoleptic tests for sweet taste led to the procurement of samples ofPiper marginatum (dried leaves),Tagetes filicifolia (fresh whole plants),Osmorhiza longistylis (fresh roots),Foeniculum vulgare (fresh aerial parts),Myrrhis odorata (fresh whole plants),Ocimum basilicum (fresh aerial parts), andIllicium verum (dried fruits). Follow-up laboratory studies of the leaves ofPiper marginatum demonstrated that trans-anethole (a phenylpropanoid) was the major sweet constituent of this species. In the remaining six species, GC/MS analysis also enabled us to demonstrate that sweetness is attributable, in each case, to the presence of high concentrations of the phenylpropanoids, trans-anethole and estragole, either alone or in combination.ResumenEntrevistas y busqueda en el campo seguidas por pruebas organolépticas para detectar el sabor dulce nos dirigieron a la adquisición de muestras dePiper marginatum (hojas secas),Tagetes filicifolia (plantas enteras secas), Osmorhiza longistylis (raices frescas),Foeniculum vulgare (partes aéreas frescas),Myrrhis odorata (plantas enteras frescas),Ocimum basilicum (partes aéreas frescas), eIllicium verum (frutas secas). Estudios de laboratorio posterioresde las hojas dePiper marginatum demostraron quetrans-anetol (un fenilpropanoide) fué el principio edulcorante mayor de esta especie. En las seis especies restantes, el análisis por medio de la cromatografía gaseosa y espectrometría de masa nos permitieron a demostrar que el sabor dulce se debe tambien, en cada caso, a la presencia de altas concentraciones de fenilpropanoides, a sabertrans-anetol y estragol, tanto sólo como en conjunto.

Orevactaene,1 a novel binding inhibitor of HIV-1 rev protein to Rev response element (RRE) from Epicoccum nigrum WC47880

Orevactaene (1), a novel oxopolyene, was isolated from Epicoccum nigrum WC47880 during the screening of microbial fermentation extracts for their ability to inhibit the binding between HIV-1 regulatory protein Rev and its viral RNA-binding site, Rev response element (RRE). The structure of 1 was elucidated by spectroscopic methods. Compound 1 displayed inhibitory activity against the Rev/RRE binding with an IC50 value of 3.6 μM.

Gaudichaudiosides A–E, five novel diterpene glycoside constituents from the sweet-tasting plant, Baccharis gaudichaudiana

A new potently sweet labdane diterpene arabinoside, gaudichaudioside A (1), was isolated from the aerial parts of Baccharis gaudichaudiana DC. (Compositae). Also isolated were four other novel labdane arabinosides, gaudichaudiosides B–E (2–5), which although closely related to 1 structurally, were not found to be highly sweet.

Unambiguous carbon-13 NMR assignments of some biologically active photoberberine alkaloids

Unambiguous proton and carbon-13 nmr chemical shifts of the protoberberine quaternary alkaloids palmatine and jatrorrhizine, their tetrahydro derivatives and tetrahydroberberine have been determined-through the use of 2D, CSCM 1D and selective INEPT nmr techniques

Alkaloid distribution in seeds of Ormosia, Pericopsis and Haplormosia

Abstract Alkaloid profiles were determined by capillary gas chromatography/mass spectrometry in seeds of 15 Ormosia species, of both South American and Asian origin, as well as in three Pericopsis species and Haplormosia monophylla . All samples contained alkaloids, and a total of 31 compounds were identified, comprising 23 lupine-type and seven Ormosia -type quinolizidine alkaloids, and the dipiperidine alkaloid, ammodendrine. Homopodopetaline, which has not previously been characterized as a natural product, was detected in extracts prepared from O. coutinhoi , O. macrophylla and O. semicastrata seeds. Ormosia -type quinolizidine alkaloids were restricted to the genus Ormosia , but were not observed in four members of this genus. The Pericopsis species accumulated predominantly α-pyridone quinolizidine bases, while two collections of H. monophylla contained mainly lupine-type quinolizidine alkaloids of the sparteine/lupanine class.

Estrous cycle dependence of nitrosomethylurea (NMU)-induced preneoplastic lesions in rat mammary gland

Virgin 50-55-day-old rats exhibiting regular estrous cycles were injected i.v. with the direct acting carcinogen 1-nitroso-1-methylurea (NMU) on the morning of proestrus, estrus, or diestrus. Rats were killed at weekly intervals following NMU administration to identify source and number of microscopically identifiable dysplasias. Terminal end bud (TEB) abnormalities appeared within 1 week following NMU administration, with a significantly greater number of abnormal TEBs in mammary glands of rats injected on proestrus (PE) and estrus (E) than on diestrus (DE). Ductal (DH) and ductal alveolar hyperplasias (DAH) and hyperplastic alveolar nodules (HAN) appeared during week 3, with significantly more of each type of lesion appearing by 6 weeks after NMU injection. HAN were most numerous in glands from rats injected on estrus. Adenocarcinomas arose from both the proximal and distal ductal network; at 10 and 12 weeks post NMU, significantly more tumors were found in rats injected on proestrus than diestrus and estrus. These results support the theory that the hormonal environment at the time of NMU administration significantly alters early development of mammary tumors in the rat.

Analysis of structural features responsible for the sweetness of the sesquiterpene, hernandulcin

The relationship between sweetness and structure was studied for several analogues of the intensely sweet sesquiterpene, hernandulcin. These derivatives were prepared synthetically, and were subjected to spectroscopic and conformational analysis. With the exception of the parent substance, none of the derivatives tested proved to be sweet. Evidence gathered in this study suggests that hernandulcin binds to its putative receptor through a three-point interaction, involving the C-1 carbonyl and C-1′ hydroxyl groups, and the double bond between C-4′ and C-5′. In the course of a preliminary safety assessment, the 3-desmethyl derivative of hernandulcin was found to be mutagenic towardSalmonella typhimurium strain TM677.

Estrous cycle modulation of O6-alkylguanine-DNA alkyltransferase expression in rat mammary epithelial cells

N-methyl-N-nitrosourea (MNU)-induced rat mammary tumor incidence and tumor number per rat, is directly correlated with an increase in the circulating level of estrogen(s) at the time of carcinogen administration and subsequent mammary epithelial O6-methylguanine content. We report that, expression of O6-alkyltransferase (AGT) is also regulated by reproductive hormones in a tissue specific manner. The level of mammary epithelial cell AGT activity on estrus (0.47 pmol/mg protein) and proestrus (0.32) was significantly higher than on metestrus (0.14) (P < 0.05, estrus vs. metestrus). However, no change was observed in liver AGT activity (0.52 pmol/mg protein). In contrast, the mean level of AGT protein was not significantly different between tumors from rats injected with MNU on different days of the estrous cycle. In conclusion, the different tumor biologies resulting from carcinogen injection on different days of the estrous cycle may be partially explained by variation in levels of DNA repair activity. However, the cells in the resulting tumors did not continue an obligatory differential expression of the AGT activity consistent with their stage of initiation.

Flavonoids from Flindersia australis

Abstract Dihydrokaempferol, dihydrokaempferol 3-O-rhamnoside (engeletin) and kaempferol were isolated from the stem bark of Flindersia australis. This is the first report of the occurrence of these flavonoids in Flindersia.