Discovery of Oral Anticancer 1,2-Bis(hydroxymethyl)benzo[g]pyrrolo[2,1-a]phthalazine Hybrids That Inhibit Angiogenesis and Induce DNA Cross-Links.

Designing hybrid molecules with dual functions is one approach to improve the therapeutic efficacy of combination treatment. We have previously conjugated phthalazine and bis(hydroxymethyl)pyrrole pharmacophores to form hybrids bearing antiangiogenesis and DNA interstrand cross-linking activities. To improve the bioavailability, we adopted a benzology approach to design and synthesize a new series of 1,2-bis(hydroxymethyl)benzo[g]pyrrolo[2,1-a]phthalazines. These new hybrids retained the dual functions and could be formulated into vehicles for intravenous and oral administration. Among them, we demonstrated that compound 19a with dimethylamine at the C6 position markedly suppressed the tumor growth of human small cell lung cancer cell line H526, squamous lung cancer cell line H520, and renal cancer cell line 786-O in nude mice, implying that compound 19a is a broad-spectrum anticancer agent. Our results implicated that the conjugation of antiangiogenic and DNA cross-linking is likely to be a helpful approach to improving the efficacy of combination therapy.

Steroid and fatty acid contents from the leaves of Carica papaya.

AIM: To extract and identify the non-polar entities from the leaves of Carica papaya, a plant used for medicinal purpose as folk medicine. MATERIALS AND METHODS: Petroleum ether extract of the Carica papaya leaves was used for this study. Saponification process and methylation process was performed to separate fatty acids and unsaponifiable matters. Phytochemical constituents were separated using chemical process and separated fractions were analyzed by thin layer chromatography (TLC) and gas chromatography coupled with mass spectroscopy (GC-MS). RESULTS: The chemical composition of the steroids, triterpenoids and fatty acid methyl esters (FAMEs) in leaves of Carica papaya, which were analyzed by gas chromatography coupled with mass spectroscopy (GC-MS). A total of 15 fatty acid components were identified in saponifiable matter, from unsaponifiable portion 2 steroids (campesterol, ß- or γ-sitosterol), 1 triterpene (squalene), and 1 diterpene (phytol) were identified. CONCLUSIONS: The results indicate that the extract is rich in non-polar compounds. In this study, GC-MS method is at the central focus for identification of these phytoconstituents. The current method can be used for direct analysis of non-polar entities of plant material.

Design, synthesis and antitumour evaluation of pyrrolo[1,2-f]-phenanthridine and dibenzo[f,h]pyrrolo[1,2-b]isoquinoline derivatives.

A series of 1,2-bis(hydroxymethyl)pyrrolo[1,2-f]phenanthridine derivatives and their alkyl (ethyl and isopropyl) carbamates and 12,13-bis(hydroxymethyl)-9,14-dihydro-dibenzo[f,h]pyrrolo[1,2-b]isoquinoline derivatives were synthesized for antiproliferative evaluation. The preliminary antitumour studies revealed that these two types of bis(hydroxymethyl) derivatives showed significant antitumour activities and were able to inhibit the growth of various human tumour cell lines in vitro. Several of the derivatives were demonstrated to cause DNA interstrand cross-links by an alkaline agarose gel shifting assay. These conjugates were cytotoxic to a variety of cancer cell lines by inducing DNA damage, delaying cell cycle progression in the G2/M phase and triggering apoptosis. Compound 21a, dissolved in a vehicle suitable for intravenous administration, was selected for antitumour studies in animal models. We demonstrated that at a dose that did not cause body weight loss in mice, compound 21a could significantly suppress the growth of tumour xenografts of human lung cancer H460 and colorectal cancer HCT-116 cells in nude mice. Our present results confirm the antitumour activities of these conjugates.

Design and Synthesis of 1,2-Bis(hydroxymethyl)pyrrolo[2,1- a]phthalazine Hybrids as Potent Anticancer Agents that Inhibit Angiogenesis and Induce DNA Interstrand Cross-links.

Hybrid molecules are composed of two pharmacophores with different biological activities. Here, we conjugated phthalazine moieties (antiangiogenetic pharmacophore) and bis(hydroxymethyl)pyrrole moieties (DNA cross-linking agent) to form a series of bis(hydroxymethyl)pyrrolo[2,1- a]phthalazine hybrids. These conjugates were cytotoxic to a variety of cancer cell lines by inducing DNA damage, arresting cell cycle progression at the G2/M phase, triggering apoptosis, and inhibiting vascular endothelial growth factor receptor 2 (VEGFR-2) in endothelial cells. Among them, compound 29d encapsulated in a liposomal formulation (e.g., 29dL) significantly suppressed the growth of small-cell lung cancer cell (H526) xenografts in mice. Based on immunohistochemical staining, the tumor xenografts in mice treated with 29dL showed time-dependent decreases in the intensity of CD31, a marker of blood vessels, whereas the intensity of γ-H2AX, a marker of DNA damage, increased. The present data revealed that the conjugation of antiangiogenic and DNA-damaging agents can generate potential hybrid agents for cancer treatment.

Triterpenoid and Fatty Acid Contents from the Stem Bark of Cordia dichotoma (Forst f.).

AIM: To isolate and determine the chemical constituents of the stem bark of Cordia dichotoma (Forst f.), a plant used for medicinal purpose in folk medicine. MATERIALS AND METHODS: Petroleum ether extract of the stem bark was used for this study. Saponification process was performed to separate fatty acid and unsaponifiable matter. RESULTS: One triterpenoids, α-amyrin was isolated from the bark by using isocratic elution. The chemical compounds isolated, for the first time, were analyzed by GC/MS, IR, and UV. The chemical composition of the fatty acids methyl esters (FAMEs) in bark of Cordia dichotoma were also analyzed by gas chromatography-mass spectrometry. After methyl-esterification, 17 components were identified in the bark. The derivatization conditions were investigated in order to validate this method. CONCLUSION: The present analysis revealed that Cordia dichotoma stem bark contains 17 fatty acid. The principal themes of the review highlight the development and application of chromatographic techniques for the separation, isolation and detection of the compounds.