Projects That Assist with Content in a Traditional Organic Chemistry Course

Projects that engage undergraduate students in content-based courses, such as organic chemistry, must relate to the material and provide useful tools for the divergent needs of the students. There are few examples of these types of projects in the literature. Herein, we describe two projects, the reaction notebook and the end-of-semester synthesis activity. Each project is designed to stimulate student ownership of the material and leads to engagement with the content of the course

A Flexible Solvolysis Experiment for the Undergraduate Organic Laboratory

A simple SN1 reaction is presented that uses bromotriphenylmethane and a range of oxygen-based nucleophiles including water and various alcohols. This procedure represents a process that affords easy isolation of solid products. Typical student yields ranged from 17–128% with the average yield of 50%. Students obtained products with a melting point range of 140 to 164 °C. This procedure offers multiple ways to adapt this experiment from a straight solvolysis reaction to a discovery-based experiment that explores the effect of nucleophile (for a more advanced group) or the method of product isolation

Technology for the Organic Chemist: Three Exploratory Modules

The ability to use computer-based technology is an essential skill set for students majoring in chemistry. This exercise details the introduction of appropriate uses for this technology in the organic chemistry series. The incorporation of chemically appropriate online resources (module 1), scientific databases (module 2), and the use of a chemical drawing program (module 3) are detailed here

Unexpected Syntheses of \u3cem\u3eseco\u3c/em\u3e-Cyclopropyltetrahydroquinolines From a Radical 5-\u3cem\u3eExo-Trig\u3c/em\u3e Cyclization Reaction: Analogs of CC-1065 and the Duocarmycins

Analogs of the seco-cyclopyrroloindoline (seco-CPI), the DNA alkylation pharmacophore of CC-1065 and the duocarmycins, can be prepared through a 5-exo-trig radical cyclization of a free radical and a 3-chloro-2-allylic moiety. This manuscript reports an unexpected discovery that, depending on the structure and stability of the free radical, the cyclization process leads to the production of an appreciable amount of seco- cyclopropyltetrahydroquinolines 7a-d along with the seco-cyclopropoyltetra- hydroindoline products (6a-e). For instance, free radical reaction of the bromoallylic chloride 5a produced an equal amount of 6-benzyloxy-N-t-butoxycarbonyl-3- (chloromethyl)furanoe]indoline (6a), and 7-benzyloxy-N-t-butoxycarbonyl-3-chloro- 1,2,3,4-tetrahydrofuranof]quinoline (7a). Three other examples that produced mixtures of indoline and quinoline products are provided. In only one of the examples reported in this manuscript, the 6-benzyloxy-N-t-butoxycarbonyl-3-(chloromethyl)benzoe]indoline, was a seco-CBI precursor 6e formed exclusively, consistent with literature precedents

A novel class of in vivo active anticancer agents: achiral \u3cem\u3eseco\u3c/em\u3e-amino- and \u3cem\u3eseco\u3c/em\u3e-hydroxycyclopropylbenz[\u3cem\u3ee\u3c/em\u3e]indolone (\u3cem\u3eseco\u3c/em\u3e-CBI) analogues of the duocarmycins and CC-1065

One achiral seco-hydroxycyclopropylbenze]indolone (seco-CBI) (12) and seven achiral seco-amino-CBI (11a-g) analogues of CC-1065 and the duocarmycins were designed, synthesized and evaluated for their DNA-binding and anticancer properties. These compounds contain a core 2-chloroethylnaphthalene structure and they do not have a stereocenter. From thermal cleavage gel analyses, compounds 11a-g and 12 demonstrated similar covalent sequence specificity to adozelesin 3 and the racemic seco-CBI-TMI 4 for binding to the 5\u27-AAAAA(865)-3\u27 site. Continuous exposure of human (K562) and murine (B16, L1210 and P815) cancer cell lines to the compounds demonstrated their significant cytotoxicity, with IC50 values in the sub-micromolar range. Generally, a good leaving group on the ethyl moiety and a free amino or hydroxyl group on the naphthyl moiety are essential for activity. According to NCI\u27s cytotoxicity screen, compounds 11a and 12 were active against human cancer cell lines derived from lung, colon, melanoma, renal system, and breast. At the respective doses of 15 and 20 mg/kg (administered via an ip route), compounds 11a and 12 inhibited the growth of murine B16-F0 melanoma in C57BL/6 mice, with minimal toxicity, and 11a gave a significant anticancer effect. The in vivo anticancer activity of compound 11a was confirmed in a human tumor xenograft study (advanced stage SC-OVCAR-3 ovarian cancer growing in scid mice). Finally, compound 11a was not toxic to murine bone marrow cell growth in culture at a dose that was toxic for the previously reported compound 4

Novel furano analogues of duocarmycin C1 and C2: design, synthesis, and biological evaluation of\u3cem\u3eseco\u3c/em\u3e-iso-Cyclopropylfurano[2,3-\u3cem\u3ee\u3c/em\u3e]indoline (\u3cem\u3eseco\u3c/em\u3e-iso-CFI) and \u3cem\u3eseco\u3c/em\u3e-Cyclopropyltetrahydrofurano[2,3-\u3cem\u3ef\u3c/em\u3e]quinoline (\u3cem\u3eseco\u3c/em\u3e-CFQ) analogues

The design, synthesis and biological evaluation of novel seco-iso-cyclopropylfurano2,3-e]indoline (seco-iso-CFI) and the seco-cyclopropyltetrahydrofurano2,3-f]quinoline (seco-CFQ) analogues of the duocarmycins are described. These novel analogues (4-7) were designed on the premise that the lone pair of electrons on the furano-oxygen atom could enter into conjugation with the isocyclopropylfuranoe]indolone (iso-CFI) alkylating moiety, formed from the loss of HCl in compounds 4-7. The seco-iso-CFI DNA alkylating pharmacophore was synthesized through a well precedented approach of 5-exo-trig aryl radical cyclization with a vinyl chloride. In our studies, in addition to the formation of the seco-iso-CFI product, an equal amount of an unexpected seco-CFQ product was also generated during the radical cyclization reaction. Like CC-1065 and adozelesin, using Taq DNA polymerase stop and thermal cleavage assays, the seco-iso-CFI compounds (4 and 6) and the seco-CFQ compounds (5 and 7) were shown to preferentially alkylate the adenine-N3 position within the minor groove of long stretches of A residues. A MM2 energy optimized molecular model of a 1:1 complex of compound 6 with DNA reveals that the iso-CFI compound fits snugly within the minor groove. Using a MTT based experiment, the cytotoxicity of compounds 4-7 were determined against the growth of murine leukemia (L1210), mastocytoma (P815) and melanoma (B16) cell lines. The concentrations of compounds required to inhibit the growth of these tumor cells by 50% is in the range of 10-ˆ’8M. These compounds were also tested against a panel of human cancer cells by the National Cancer Institute, demonstrating that the compounds exhibited a high level of activity against selected solid tumors. At a concentration of 0.0084μM (based on the IC50 of compound 17 (seco-CBI-TMI) against the growth L1210 cells), while compounds 4 and 17 were toxic against murine bone marrow cells as judged by a colony forming study of freshly isolated murine progenitor hematopoeitic cells, compound 5, a seco-CFQ compound, was significantly less toxic. Flow cytometric analysis of P815 cells that had been incubated for 24h with compounds 4 and 5 at their cytotoxic IC50 concentrations indicated the induction of apoptosis in a large percentage of cells, thereby suggesting that this might be the mechanism by which the iso-CFI compounds kill cells