Intensified research interests are posed with the thionucleobase 4-thiouracil (4-TU), due to its important biological function as site-specific photoprobe to detect RNA structures and nucleic acid-nucleic acid contacts. By means of time-resolved IR spectroscopy and density functional theory (DFT) studies, we have examined the unique photophysical and photochemical properties of 4-TU. It is shown that 4-TU absorbs UVA light and results in the triplet formation with a high quantum yield (0.9). Under N2-saturated anaerobic conditions, the reactive triplet undergoes mainly cross-linking, leading to the (5-4)/(6-4) pyrimidine-pyrimidone product. In the presence of O2 under aerobic conditions, the triplet 4-TU acts as an energy donor to produce singlet oxygen (1)O2 by triplet-triplet energy transfer. The highly reactive oxygen species (1)O2 then reacts readily with 4-TU, leading to the products of uracil (U) with a yield of 0.2 and uracil-6-sulfonate (U(SO3)) that is fluorescent at ~390 nm. The product formation pathways and product distribution are well rationalized by the joint B3LYP/6-311+G(d,p) calculations. From dynamics and mechanistic point of views, these results enable a further understanding for 4-TU acting as reactive precursors for photochemical reactions relevant to (1)O2, which has profound implications for photo cross-linking, DNA photodamage, as well as photodynamic therapy studies.

As an end metabolism product of the widely used thiopurine drugs, 6-thioguanine (6-TG) absorbs UVA and produces (1)O2 by photosensitization. This unusual photochemical property triggers a variety of DNA damage, among which the oxidation of 6-TG itself by (1)O2 to the promutagenic product guanine-6-sulfonate (G(SO3)) represents one of the major forms. It has been suspected that there exists an initial intermediate, G(SO), prior to its further oxidation to G(SO2) and G(SO3), but G(SO) has never been observed. Using density functional theory, we have explored the energetics and intermediates of 6-TG and (1)O2. A new mechanism via G(SOOH) → G(SO2) → G(SO4) → G(SO3) has been discovered to be the most feasible energetically, whereas the anticipated G(SO) mechanism is found to encounter an inaccessibly high barrier and thus is prevented. The mechanism through the G(SOOH) and G(SO4) intermediates can be validated further by joint experimental measurements, where the fast rate constant of 4.9 × 10(9) M(-1) s(-1) and the reaction stoichiometry of 0.58 supports this low-barrier new mechanism. In addition to the dominant pathway of G(SOOH) → G(SO2) → G(SO4) → G(SO3), a side pathway with higher barrier, G(SOOH) → G, has also been located, providing a rationalization for the observed product distributions of G(SO2) and G(SO3) as major products and G as minor product. From mechanistic and kinetics points of view, the present findings provide new chemical insights to understand the high phototoxicity of 6-TG in DNA and point to methods of using 6-TG as a sensitive fluorescence probe for the quantitative detection of (1)O2, which holds particular promise for detecting (1)O2 in DNA-related biological surroundings.

Learning nature's approach to modulate photophysical properties of NIR porphyrinoids by fine-tuning β-substituents including the number and position, in a manner similar to naturally occurring chlorophylls, has the potential to circumvent the disadvantages of traditional "extended π-conjugation" strategy such as stability, molecular size, solubility, and undesirable π-π stacking. Here we show that such subtle structural changes in Pt(II) or Pd(II) cis/trans-porphodilactones (termed by cis/trans-Pt/Pd) influence photophysical properties of the lowest triplet excited states including phosphorescence, Stokes shifts, and even photosensitization ability in triplet-triplet annihilation reactions with rubrene. Prominently, the overall upconversion capability (η, η = ε·Φ(UC)) of Pd or Pt trans-complex is 10(4) times higher than that of cis-analogue. Nanosecond time-resolved infrared (TR-IR) spectroscopy experiments showed larger frequency shift of ν(C═O) bands (ca. 10 cm(-1)) of cis-complexes than those of trans-complexes in the triplet excited states. These spectral features, combining with TD-DFT calculations, suggest the strong electronic coupling between the lactone moieties and the main porphyrin chromophores and thus the importance of precisely positioning β-substituents by mimicking chlorophylls, as an alternative to "extended π-conjugation", in designing NIR active porphyrinoids.

Cancer therapeutic strategies based on angiogenesis attract great attention from fundamental and clinical research. Blocking oxygen and nutrition supply to tumor cells could inhibit the growth of tumors based on occlusion of blood vessels in the tumor. Herein, we report a dual-responsive peptide-based nanoparticle, mimicking the laminin fibrillogenesis specifically and highly efficiently in tumor vessels, resulting in the blockage of tumor vessels and the growth inhibition of tumors. The laminin mimic peptide (LMMP) is designed with a fibrillation sequence, a pH-responsive sequence, and a targeting sequence. The LMMP in nanoformulations is delivered to blood vessels in the tumors, where the microenvironment (pH and microthrombus) enable LMMP to process laminin fibrillogenesis, constructing fibrous networks. The laminin-like fibrous networks capture red blood cells etc., forming occlusion specifically in the tumor blood vessels to inhibit the growth of the tumor.

Aberrant change in long noncoding RNA (lncRNA) is associated with various diseases and cancers. So far, simultaneous detection of lncRNAs has remained a great challenge due to their large size and extensive secondary structure. Herein, we develop an enzyme-free single-molecule/particle detection method for simultaneous detection of multiple lncRNAs in cancer cells based on target-catalyzed strand displacement. We designed the magnetic bead–capture probe–multiple Cy5/Cy3-modified reporter unit complexes to isolate and identify lncRNA MALAT1 and lncRNA HOTAIR. The target-catalyzed strand displacement reactions lead to the release of Cy5 and Cy3 fluorescent molecules from the complexes, which can be subsequently quantified by single-molecule/particle detection. The dual-targetability, good selectivity and high sensitivity of this method enables simultaneous detection of multiple lncRNAs in even single cancer cell. Importantly, this method can discriminate cancer cells from normal cells and has significant advantages in the simple sequence design and in being free of enzymes, holding great potential in living cell imaging and early clinical diagnosis.

Multiple nonadiabatic pathways greatly facilitate the proceeding of photocrosslinking reactions between 4-thiopyrimidine and thymine.

Telomerase is a highly valuable cancer diagnosis biomarker and a promising cancer therapy target. So far, most telomerase assays are limited by the involvement of tedious procedures, multiple enzymes, and complicated reaction schemes. Sensitive monitoring of low-abundant telomerase in living cells remains a challenge. Herein, we demonstrate an entropy-driven catalytic assembly of quantum dot (QD) sensors for accurate detection and imaging of telomerase activity in living cells. In this sensor, target telomerase specifically catalyzes extension of telomerase primer, and the extended primer subsequently acts as a catalyst to continuously initiate entropy-driven catalytic reaction, generating a large number of fluorophore-and biotin-labeled DNAs that can be self-assembled on the QD surface to induce an efficient Foster resonance energy transfer signal. The proposed sensor requires a single step for both recognition and amplification of the telomerase signal, eliminating the use of either protein enzymes or laborious procedures. Taking advantage of the inherent superiority of single-molecule fluorescence detection and high amplification efficiency of the entropy-driven reaction, this sensor demonstrates single-cell sensitivity for the in vitro assay. Moreover, it is capable of screening the telomerase inhibitor, discriminating different tumor cells from normal ones, and even real-time imaging telomerase in living cells, providing a novel platform for telomerase-associated cancer diagnosis and drug screening.

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