Evaluation of 5-hydroxy-2,3-diaryl (substituted)-cyclopent-2-en-1-ones as cis-restricted analogues of combretastatin A-4 as novel anti angiogenic and anticancer agents.

Two potent cis-restricted CA-4 analogues 11 and 42 belonging to 2,3-diaryl-5-hydroxycyclopent-2-en-1-one class were evaluated for anticancer and anti angiogenic activity. The compound 42 displayed potent cytotoxic activity (IC(50) < 1 muM) against a panel of human cancer cell lines viz PTC, MDA.MB.453, PA1, SKOV3, DU145 and Miapaca2, whereas compound 11 displayed cytotoxicity activity (IC(50) < 1 microM) only in Miapaca2. Both the compounds inhibit growth factor stimulated endothelial cell proliferation, migration and capillary tube formation. In all the above parameter compound 42 was superior to 11. Based on the above results compound 42 was assessed for inhibition of vasculature in vivo and showed significant inhibition at 25 mg/kg dose. Further it was evaluated for in vivo anti tumor activity in athymic mice bearing DU145 and SKVO3 tumor xenograft and showed regression in tumor volume (T/C) of 23.8% (CA-4), 50.1% (compound 42) and 23.5% (CA-4), 56% (compound 42) respectively at a dose of 20 mg/kg (i.v.) daily for 14 days.

Eclipta alba extract with potential for hair growth promoting activity.

ETHNOPHARMACOLOGICAL RELEVANCE: Eclipta alba is traditionally known to potentiate hair growth promotion. AIM OF THE STUDY: The study was aimed to investigate the efficacy of methanol extract of Eclipta alba as hair growth promoter. MATERIALS AND METHODS: Pigmented C57/BL6 mice, preselected for their telogen phase of hair growth were used. In these species, the truncal epidermis lacks melanin-producing melanocytes and melanin production is strictly coupled to anagen phase of hair growth. The extract was applied topically to assess telogen to anagen transition. Immunohistochemical investigation was performed to analyze antigen specificity. Animals in anagen phase of hair growth were positive for FGF-7 and Shh and negative for BMP4, whereas the animals in telogen phase were positive only for BMP4 antigen. RESULTS: The methanol extract of whole plant when tested for hair growth promoting potential, exhibited dose dependent activity in C57BL6 mice. The activity was assessed by studying the melanogenesis in resected skin, follicle count in the subcutis, skin thickness and surrogate markers in vehicle control and extract treated animals. CONCLUSION: These findings suggest that methanol extract of Eclipta alba may have potential as a hair growth promoter.

Anticancer and immunomodulatory activities of novel 1,8-naphthyridine derivatives.

A number of 1,8-naphthyridine derivatives (22-62) have been synthesized and screened for their in vitro cytotoxicity against eight tumors and two non-tumor cell lines. Halogen substituted 1,8-naphthyridine-3-caboxamide derivatives showed potent activity with compound 47 having IC(50) of 0.41 and 0.77 microM on MIAPaCa and K-562 cancer cell lines, respectively while, compound 36 had IC(50) of 1.19 microM on PA-1 cancer cell line. However, one of the unsubstituted 1,8-naphthyridine-C-3'-heteroaryl derivative 29 showed potent cytotoxicity with IC(50) of 0.41 and 1.4 microM on PA-1 and SW620 cancer cell lines, respectively. These compounds were also evaluated for anti-inflammatory activity as suggested by downregulation of proinflammaotory cytokines.

1,8-Naphthyridine-3-carboxamide derivatives with anticancer and anti-inflammatory activity.

A number of 1-propargyl-1,8-naphthyridine-3-carboxamide derivatives (15-35) have been synthesized and screened for their in vitro cytotoxicity and anti-inflammatory activity. Compounds 22, 31 and 34 have shown high cytotoxicity against a number of cancer cell lines, while compound 24 showed significant anti-inflammatory activity.

Synthesis of quinazolines as tyrosine kinase inhibitors.

In the present review, the discovery and development of quinazoline as tyrosine kinase inhibitors has been described. The synthesis of most potent quinazoline inhibitors of EGFR, VEGFR and PDGRF has been discussed. Structure activity relationship for quinazoline as tyrosine kinase inhibitors has been established. It was found that C-4, C-6 and C-7 positions in quinazoline are appropriate sites for designing new tyrosine kinase inhibitors. This review should help the medicinal chemist in designing more effective tyrosine kinase inhibitors.

Quercetin and its derivatives: synthesis, pharmacological uses with special emphasis on anti-tumor properties and prodrug with enhanced bio-availability.

Cancer is one of the leading causes of death in the world. American Cancer Society reported 12 million new cases of malignancy diagnosed worldwide in 2007, with 7.6 million people dying from the disease. Plant-derived molecules have played an important role in cancer chemotherapy. Many cytotoxic plant-derived molecules such as vinblastine, vincristine, navelbine, etoposide, teniposide, taxol, taxotere, topotecan and irinotecan have been approved as anticancer drugs. Flavonoids, a plant-derived molecule has shown to regulate proliferation and cell death pathways leading to cancer. Some Flavonoids have already entered in clinical trials, among them Quercetin is emerging as prospective anticancer drug candidates and its prodrug QC12 has entered in phase-I clinical studies. In this review authors have tried to cover in brief but comprehensive way, the chemistry related to synthesis and uses of "Quercetin & its derivatives" with special emphasis on the anticancer properties.

Synthesis of functionalized amino acid derivatives as new pharmacophores for designing anticancer agents.

A new series of functionalized amino acid derivatives N-substituted 1-N-(tert-butoxycarbonyl)-2,2-dimethyl-4-phenyl-5-oxazolidine carboxamide (1-17) and 1-N-substituted-3-amino-2-hydroxy-3-phenylpropane-1-carboxamide (18-34) were synthesized and evaluated for their in vitro cytotoxicity against human cancer cell lines. Compound 6 has shown interesting cytotoxicity (IC(50) = 5.67 microm) in ovarian cancer, while compound 10 exhibited promising cytotoxicity in ovarian (IC(50) = 6.1 microm) and oral (IC(50) = 4.17 microm) cancers. These compounds could be of use in designing new anti-cancer agents.

Synthesis and cytotoxic activity of heterocyclic ring-substituted betulinic acid derivatives.

A new series of betulinic acid derivatives have been synthesized by introducing heterocyclic ring between C-2 and C-3 positions of betulinic acid. Further modifications were also carried out by reduction of C-20(29) unsaturated bond and substitution of C-28 carboxyl group by ester and amide linkage to enhance the selectivity. Compound 11 resulted in IC(50) of 2.44, 2.5, and 2.7 microg/ml on MIAPaCa, PA-1, and SW620 cancer cell lines, respectively. Compound 38 resulted in IC(50) of 0.67 microg/ml on MIAPaCa cell line.

Protective effects of Terminalia arjuna against Doxorubicin-induced cardiotoxicity.

Terminalia arjuna has been marked as a potential cardioprotective agent since vedic period. The present study was aimed to investigate the effects of butanolic fraction of Terminalia arjuna bark (TA-05) on Doxorubicin (Dox)-induced cardiotoxicity. Male wistar rats were used as in vivo model for the study. TA-05 was administered orally to Wistar rats at different doses (0.42 mg/kg, 0.85 mg/kg, 1.7 mg/kg, 3.4 mg/kg and 6.8 mg/kg) for 6 days/week for 4 weeks. Thereafter, all the animals except saline and TA-05-treated controls were administered 20 mg/kg Dox intraperitonially. There was a significant decrease in myocardial superoxide dismutase (38.94%) and reduced glutathione (23.84%) in animals treated with Dox. Concurrently marked increase in serum creatine kinase-MB (CKMB) activity (48.11%) as well as increase in extent of lipid peroxidation (2.55-fold) was reported. Co-treatment of TA-05 and Dox resulted in an increase in the cardiac antioxidant enzymes, decrease in serum CKMB levels and reduction in lipid peroxidation as compared to Dox-treated animals. Electron microscopic studies in Dox-treated animals revealed mitochondrial swelling, Z-band disarray, focal dilatation of smooth endoplasmic reticulum (SER) and lipid inclusions, whereas the concurrent administration of TA-05 led to a lesser degree of Dox-induced histological alterations. These findings suggest that butanolic fraction of Terminalia arjuna bark has protective effects against Dox-induced cardiotoxicity and may have potential as a cardioprotective agent.

Modulation of key signal transduction molecules by a novel peptide combination effective for the treatment of gastrointestinal carcinomas.

We have reported earlier a novel combination of four structurally designed synthetic neuropeptide analogs of vasoactive intestinal peptide (VIP), bombesin, substance P and somatostatin, code-named DRF 7295 which have anti-tumor efficacy for adenocarcinomas in vitro and in vivo (Jaggi et al., Invest New Drugs, 2008). The discovery, synthesis, in vitro and in vivo efficacy was reported (Jaggi et al., Invest New Drugs, 2008). Gastrointestinal tumor cells of the colon, pancreas and duodenum were found to most sensitive to DRF7295 in vitro and in vivo (Jaggi et al., Invest New Drugs, 2008). We have further investigated and report here the modulation of cellular signaling in gastrointestinal carcinomas by DRF 7295, which may be mediating its observed anticancer activity in these cancer types. DRF 7295 inhibits the binding of specific neuropeptides initiating a cascade of cellular signaling events leading to programmed cell death. It down regulates the second messenger cAMP, epidermal growth factor (EGF) dependent proliferation and the phosphorylated MAP Kinase pERK1/2 in gastrointestinal carcinomas, thus depriving the tumour cells of critical pro-proliferative cellular signals. It triggers bcl2 and Caspase 3 dependent apoptotic cell death and induces p53 tumor suppressor protein in the treated carcinoma cells in vitro. It has significant anti-angiogenic potential as reflected in the inhibition of tube like formation in the endothelial cells and down regulation of VEGF levels. Tumour xenograft studies confirmed the in vivo efficacy of DRF 7295 for gastrointestinal carcinomas (Jaggi et al., Invest New Drugs, 2008). The Phase I clinical trials have shown DRF 7295 to be well tolerated and devoid of systemic toxicities of the conventional cytotoxics (Mukherjee et al., Phase I dose escalating study of DRF7295: a new class of peptide based drugs. "Abstract" ASCO ID:948, 2003). The drug may have a promising role in disease stabilization in colorectal and other cancers. Thus DRF 7295 is a novel targeted drug in the class of signal transduction modulators, with potential for treatment of gastrointestinal carcinomas.

Anticancer activity of a peptide combination in gastrointestinal cancers targeting multiple neuropeptide receptors.

A novel peptide combination consisting of four synthetic neuropeptide analogs of Vasoactive Intestinal Peptide (VIP), Bombesin, Substance P and Somatostatin has been found to have potent anticancer activity in vitro and in vivo. The receptors of these four neuropeptides are known to be over expressed in various cancers. We have found the presence of native neuropeptides in the culture supernatant of the primary tumor cells of human colon adenocarcinomas. It was further demonstrated by receptor-ligand assays that not only do these tumor cells synthesize and secrete four peptide hormones but also possess specific high affinity receptors on their surface. Screening a large panel of analogs to the four peptide hormones on tumor cell proliferation led to the identification of four cytotoxic analogs, the combination of which was code-named DRF7295. The design and synthesis of the peptide analogs have been described in this paper. In vitro anticancer activity of DRF7295 was studied in a large panel of human tumor cells. Gastrointestinal tumor cells of the colon, pancreas and duodenum were found to be most sensitive to DRF7295 with moderate activity seen in glioblastoma, prostate, leukemia and those of oral cancer cells. Efficacy studies in xenograft models of colon and duodenum resulted in T/C% of less than 40%, which is indicative of strong tumor regressing potential of DRF7295 in gastrointestinal cancers. Acute and long-term toxicity studies as well as safety pharmacology studies conducted indicate the safety of the drug upon systemic administration with no significant adverse pharmacological effects.

Pharmacological evaluation of C-3 modified Betulinic acid derivatives with potent anticancer activity.

In vitro and in vivo pharmacological screening of Betulinic acid (BA) and five dihydro-BA derivatives modified at C-3 position [4-nitrobenzyl-oximino (1), 2-4-difluoro-benzoyloxy (2), 2-4-difluoro-benzylidene-amino (3), benzoyl-hydrazono (4), and 4-fluorophenyl-hydrazono (5)], having potent in vitro anti-cancer activity was carried out using ADME, animal PK and tumor studies. We found that BA and the derivatives had poor aqueous solubility (<0.1 microg/ml), low to moderate permeability (log Pe<-5.0) and high plasma protein binding (>70%). Although BA and 5 were metabolized by human liver microsomes, derivatives 1, 2, 3 and 4 possessed good in vitro metabolic stability. Except 3 which inhibited CYP1A2 isoform by more than 50% none of the other compounds inhibited key cytochrome P450 enzyme isoforms (CYP1A2, CYP2C9, CYP2D6 and CYP3A4) at 10 microM. Based on in vitro results one derivative 1 was tested in rodent PK and tumor studies. We found that 1 exhibited favorable pharmacokinetic characteristics of a systemically administered drug and showed better in vivo anti-tumor efficacy as compared to BA in a human colon cancer xenograft model. Our results show that BA derivatives are potential anti-cancer compounds which need to be explored in detail.

Synthesis and structure-activity relationships of potent antitumor active quinoline and naphthyridine derivatives.

The disease of cancer has been ranked second after cardiovascular diseases and plant-derived molecules have played an important role for the treatment of cancer. Nine cytotoxic plant-derived molecules such as vinblastine, vincristine, navelbine, etoposide, teniposide, taxol, taxotere, topotecan and irinotecan have been approved as anticancer drugs. Recently, epothilones are being emerging as future potential anti-tumor agents. However, targeted cancer therapy has now been rapidly expanding and small organic molecules are being exploited for this purpose. Amongst target specific small organic molecules, quinazoline was found as one of the most successful chemical class in cancer chemotherapy as three drugs namely Gefitinib, Erlotinib and Canertinib belong to this series. Now, quinazoline related chemical classes such as quinolines and naphthyridines are being exploited in cancer chemotherapy and a number of molecules such as compounds EKB-569 (52), HKI-272 (78) and SNS-595 (127a) are in different phases of clinical trials. This review presents the synthesis of quinolines and naphthyridines derivatives, screened for anticancer activity since year 2000. The synthesis of most potent derivatives in each prototype has been delineated. A brief structure activity relationship for each prototype has also been discussed. It has been observed that aniline group at C-4, aminoacrylamide substituents at C-6, cyano group at C-3 and alkoxy groups at C-7 in the quinoline ring play an important role for optimal activity. While aminopyrrolidine functionality at C-7, 2'-thiazolyl at N-1 and carboxy group at C-3 in 1,8-naphthyridine ring are essential for eliciting the cytotoxicity. This review would help the medicinal chemist to design and synthesize molecules for targeted cancer chemotherapy.

Anticancer and anti-inflammatory activities of 1,8-naphthyridine-3-carboxamide derivatives.

Several 1,8-naphthyridine-3-carboxamide derivatives (8-23) were synthesized and tested for in vitro cytotoxicity against eight cancer cell lines and a normal cell line. Compound 12 exhibited high cytotoxicity (IC(50)=1.37microM) in HBL-100 (breast) cell line while compounds 17 (IC(50)=3.7microM) and 22 (IC(50)=3.0microM) have shown high cytotoxicity in KB (oral) and SW-620 (colon) cell lines, respectively. The synthesized 1,8-naphthyridine-3-carboxamides were also evaluated for anti-inflammatory and myeloprotective activities, indicated by modulation in cytokine and chemokine levels secreted by dendritic cells.

Synthesis and evaluation of 4/5-hydroxy-2,3-diaryl(substituted)-cyclopent-2-en-1-ones as cis-restricted analogues of combretastatin A-4 as novel anticancer agents.

A new series of 2,3-diaryl-4/5-hydroxy-cyclopent-2-en-1-one analogues replacing the cis double bond of combretastatin A-4 (CA-4) by 4/5-hydroxy cyclopentenone moieties was designed and synthesized. The analogues displayed potent cytotoxic activity (IC50<1 microg/mL) against a panel of human cancer cell lines and endothelial cells. The most potent analogues 11 and 42 belonging to the 5-hydroxy cyclopentenone class were further evaluated for their mechanism of action. Both of the analogues led to cell cycle arrest at G2/M phase and induced apoptosis in endothelial cells. Antitubulin property of 42 was superior to 11 and comparable to CA-4. The compound 42 had better aqueous solubility, metabolic stability, and pharmacokinetic profile than CA-4 and also demonstrated significant tumor regression in the human colon xenograft model. Our data suggests that cis-restricted analogues of CA-4 are a new class of molecules that have the potential to be developed as novel agents for the treatment of cancer.

Isolation and characterization of degradation impurities in docetaxel drug substance and its formulation.

The degradation of docetaxel drug substance and its injection formulation has been investigated. The majority of impurities were observed in a base degradation study and all five degradation products were characterized. These impurities were isolated, enriched and were subjected to mass and NMR spectral studies. Based on the spectral data, these were characterized as 10-deacetyl baccatin III, 7-epi-10-deacetyl baccatin III, 7-epi-10-oxo-10-deacetyl baccatin III, 7-epi docetaxel and 7-epi-10-oxo-docetaxel, respectively. The last two impurities were also detected in the stability study of docetaxel formulation. Out of these degradation impurities two substances have been previously identified while the other three previously unreported.

Synthesis of 13-amino costunolide derivatives as anticancer agents.

A number of costunolide derivatives (4a-p) have been synthesized and evaluated for their in vitro cytotoxicity against eight tumor and a non-tumor cell lines. Compound 4d showed around 2-fold better cytotoxicity against SW-620 (colon) cell line with improved safety index than costunolide (1). While compounds 4e, 4g, and 4p have shown around 2- to 3-fold better cytotoxicity against MIAPaCa2 (pancreas), K-562 (leukemia) and PA-1 (ovary) cell lines as well as better safety index in comparison to costunolide (1). Compound 4p also exhibited cytotoxicity against HBL100 (breast) cell line with 2-fold better safety index. Structure-activity relationship has been described.

Identification of isocephalomannine in the presence of cephalomannine isomers and alkali metal ion adducts in a paclitaxel active pharmaceutical ingredient using electrospray tandem mass spectrometry.

A strategy is developed for the identification of isocephalomannine in the presence of alkali metal ion adducts and other cephalomannine isomers in a paclitaxel active pharmaceutical ingredient. Intact molecular ion analyses and a sub-structural study have been performed for the differentiation of isocephalomannine (2-debenzoylpaclitaxel-2-pentenoate) from cephalomannine and 7-epi-cephalomannine. A comparative study of the cephalomannine isomers was carried out using molecular ions (MS) and fragmentation patterns (MS/MS) for sub-structural analysis. An attempt has been made to identify isocephalomannine in Cremophor(R) EL formulations.

Betulinic acid derivatives as anticancer agents: structure activity relationship.

Betulinic acid, a pentacyclic triterpene, is widely distributed throughout the tropics. It possesses several biological properties such as anticancer, anti-inflammatory, antiviral, antiseptic, antimalarial, spermicidal, antimicrobial, antileshmanial, antihelmentic and antifeedent activities. However, betulinic acid was highly regarded for its anticancer and anti-HIV activities. Anticancer role of betulinic acid appeared by inducing apoptosis in cells irrespective of their p53 status. Due to high order safety in betulinic acid, a number of structural modifications carried out to improve its potency and efficacy. The C-1, C-2, C-3, C-4, C-20 and C-28 positions are the diversity centers in betulinic acid, and the derivatives resulted on various structural modifications at these positions screened for their anticancer activity. This review presents the structure activity relationship carried out on C-1, C-2, C-3, C-4, C-20, C-28, A-ring, D-ring and E-ring modified betulinic acid derivatives. We have compiled the most active betulinic acid derivatives along with their activity profile in each series. Structure activity relationship studies revealed that C-28 carboxylic acid was essential for the cytotoxicity. The halo substituent at C-2 position in betulinic acid enhanced the cytotoxicity. Though the relation of the cytotoxicity with the nature of substituents at C-3 position could not be generalized but the ester functionality appeared to be a better substituent for enhancing the cytotoxicity. An interesting observation is that the three rings skeleton (A, B and C rings) had played an important role in eliciting anticancer activity, which could be a new molecular skeleton to design new anticancer drugs.

Identification of degradation products from aqueous carboplatin injection samples by electrospray mass spectrometry.

Four different carboplatin injection samples in water ( approximately 10mg/ml) stored at room temperature were investigated for degradation products by electrospray liquid chromatography-mass spectrometry (ESI/LC-MS). A mass spectrometer compatible mobile phase system with 0.02% formic acid and methanol was used to resolve the impurities. Possible chemical structures of the unknown impurities and its degradation mechanism were proposed based on its experimental results and literature findings.